TWI400074B - Condensed heterocyclic derivatives, pharmaceutical compositions containing them and their pharmaceutical use - Google Patents

Description

Condensed heterocyclic derivative, pharmaceutical composition containing the same, and medical use thereof

This invention relates to condensed heterocyclic derivatives.

More specifically, the present invention relates to gonad-stimulating hormone releasing hormone antagonism, and can be used for prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroid tumor, early onset of adolescence, no menstrual period, menstruation a condensed heterocyclic derivative such as a prophylactic or therapeutic agent for a sex-related disease such as a pre-existing syndrome or a menstrual disorder, or a prodrug thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof And pharmaceutical compositions containing the same.

Gonadotropin Releasing Hormone (GnRH, or GnRH, also known as Luteinizing Hormone Releasing Hormone: LHRH. Hereinafter referred to as "GnRH".) is secreted by the lower part of the hypothalamus. A peptide composed of an amino acid (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2). The GnRH system secreted by the portal vein of the pituitary gland promotes the gonad stimulation hormone belonging to the anterior pituitary hormone through the receptor (GnRH receptor) which is thought to exist in the anterior pituitary gland (the luteal hormone Luteinizing Hormone: LH, Egg cell stimulates the production and secretion of hormone Follicle Stimulating Hormone: FSH. These gonad-stimulating hormones act on the gonads (ovary, testis) and promote the development of egg cells, ovulation, luteinization and sperm formation, and also promote the production and secretion of sex hormones (emotional hormone, progesterone, and male hormone) (non-patented) Document 1). Therefore, since the GnRH receptor-specific and selective antagonist will regulate the action of GnRH and control the production and secretion of hormones and hormones, it is expected to be a preventive and therapeutic drug for sexual hormone-dependent diseases. .

As a drug that inhibits the function of the GnRH receptor, the GnRH receptor super agonist has been used as a therapeutic drug for a hormone-dependent disease such as prostate cancer, breast cancer, and endometriosis. The GnRH receptor super-agonist binds to the GnRH receptor and exhibits a transitional gonad-stimulating hormone secretion stimulating effect (flareup phenomenon) at the initial stage of administration, which in turn causes gonad-stimulating hormone rush and GnRH receptor The function is reduced, thereby suppressing its function. Therefore, the GnRH receptor super-agonist has a problem that the gonad-stimulated hormone secretion is advanced based on the initial administration, and the condition is temporarily deteriorated. On the other hand, the inhibitory mechanism of the GnRH receptor antagonist (hereinafter referred to as "GnRH antagonist") is that binding to the GnRH receptor is inhibited, so that it is expected that the hormone secretion is not accompanied by the secretion of hormones. In recent years, peptide peptide GnRH antagonists such as Abarelix and Cetrorelix have been developed as GnRH antagonists, and are used for treatments such as prostate cancer and infertility. However, since these peptide GnRH antagonists are difficult to be absorbed by the mouth and have to be administered subcutaneously or intramuscularly, it is expected that the local reactivity and the elasticity of the injection portion can be avoided, and Development of a non-peptide GnRH antagonist for oral administration (see Non-Patent Document 2).

Examples of the condensed pyrimidine derivatives having a non-peptidic GnRH antagonistic activity include the compounds described in Patent Documents 1 and 2. However, the compounds described in Patent Document 1 are all those having an aryl substituent on a 5-membered ring heterocyclic ring condensed with a pyrimidine ring. Further, the compound described in Patent Document 2 is a pyrimidine derivative which is condensed with an aromatic 6-membered ring, and the oral absorbability is not necessarily high. Patent Document 3 published recently discloses a pyrimidine derivative having a non-peptidic GnRH antagonistic action condensed with a 5-membered ring heterocyclic ring. However, it is not specifically described for compounds other than the compound having a sulfonamide or a guanamine group, and the blood dynamics at the time of oral administration are not specifically described.

Examples of the compound having a pyrimidine ring condensed with a 5-membered ring heterocyclic ring include, for example, Patent Document 4 as a serine protease inhibitor; Patent Document 5 as a blood coagulation factor Xa inhibitor; In Document 6, various compounds such as herbicides are used. However, in these documents, the compound having a pyrimidine ring condensed with a 5-membered ring heterocyclic ring of the present invention has a GnRH antagonistic action and is not described or taught.

Non-Patent Document 1: "Standard Physiology", Fifth Edition, Medical College, pp. 882-891 Non-Patent Document 2: "Obstetrics and Women's Division", 2004, Vol. 71, No. 3, pp. 280-285 301-307

Patent Document 1: International Publication No. 1996/24597 Annotated Patent Document 2: International Publication No. 2005/019188 Annotated Patent Document 3: International Publication No. 2006/083005 Annotated Patent Document 4: US Patent Application Publication No. 2003/ Patent Document No. 0004167 Patent Document 5: International Publication No. 00/39131 Annotated Patent Document 6: Japanese Patent Laid-Open No. Hei 6-510992

An object of the present invention is to provide a compound having GnRH antagonistic action.

The inventors of the present invention have intensively studied to solve the above problems, and as a result, it has been found for the first time that a pyrimidine derivative condensed with a 5-membered ring heterocyclic ring represented by the following general formula (I) has superior GnRH antagonistic action, compared with aroma. The 6-membered ring-condensed pyrimidine derivative exhibits excellent blood dynamics in oral administration, and the present invention has been completed.

That is, the present invention relates to [1] a condensed heterocyclic derivative or a precursor thereof or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, which is represented by the general formula (I): [wherein, ring A is a 5-membered ring-unsaturated hydrocarbon or a 5-membered ring heteroaryl; R ^A is a halogen atom, a cyano group, a nitro group, a substitutable lower alkyl group, a substitutable lower alkenyl group, a substitutable lower alkynyl group. , hydroxyiminomethyl, substitutable lower alkylsulfonyl, substitutable lower alkyl sulfinylene, tetrazolyl, OW ¹ , SW ¹ , COW ¹ , COOW ¹ , NHCOW ¹ , NHCONW ² W ³ , NW ² w ³ , CONW ² W ³ or SO ₂ NW ² W ³ (W ¹ ~ W ^{3 are} independently a hydrogen atom or a lower alkyl group, and W ² and W ³ may also be bonded to a nitrogen atom adjacent to the two. Together form a substitutable cyclic amine group; m is an integer from 0 to 3; ring B is an aryl or heteroaryl group; R ^B is a halogen atom, a cyano group, a substitutable lower alkyl group, OW ⁴ , COW ⁴ , COOW ⁴ or CONW ⁵ W ⁶ (W ⁴ ~ W ^{6 is} independently a hydrogen atom or a substitutable lower alkyl group, and W ⁵ and W ⁶ may form a substitutable cyclic amine group together with a nitrogen atom adjacent to the two;) An integer of 0 to 2; E ¹ is an oxygen atom, a sulfur atom or N-CN; E ² is an oxygen atom or NH; U is a single bond or a lower alkyl group; X is Y, -CO-Y, - SO ₂ -Y, -S-L-Y, -O-L-Y, -CO-L-Y, -COO-L a group represented by -Y, -SO-L-Y, -SO ₂ -L-Y, -S-Z, -O-Z or -COO-Z (wherein L is a substitutable lower alkyl group; Y Z or -NW ⁷ W ⁸ [W ⁷ and W ^{8 are} independently a hydrogen atom, a lower alkyl group or a Z (but not a hydrogen atom at the same time), or W ⁷ and W ⁸ may be bonded to the two. a nitrogen atom together form a group which may be substituted by a cyclic amine group; Z is a substitutable cycloalkyl group which may also be condensed, a condensed ring may be substituted a heterocycloalkyl group, or a condensed ring may be substituted aryl group Or a condensed ring-substituted heteroaryl group]; [2] The condensed heterocyclic derivative of the above [1] or a precursor thereof or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof And a condensed heterocyclic ring of the above [2] or a precursor thereof or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof And a 5-membered cycloheterocyclic ring of ring A is any one of the thiophene rings represented by the following formula; [4] The condensed heterocyclic derivative of the above [3], or a precursor thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein the 5-membered ring heteroaryl ring system of the ring A a thiophene ring represented by the following formula; [5] The condensed heterocyclic derivative of any one of the above [1] to [4], or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein R ^A is a halogen atom, a substitutable lower alkyl group, COOW ¹ or CONW ² W ³ (W ¹ to W ^{3 are} independently a hydrogen atom or a lower alkyl group, and W ² and W ³ may be bonded to a nitrogen atom adjacent to the two. [6] The condensed heterocyclic derivative of the above [5] or a precursor thereof or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, R ^A is a lower alkyl group substituted with a group selected from a hydroxyl group, a carboxyl group and an amine carbenyl group; a carboxyl group; or an amine carbenyl group; [7] a condensed heterocyclic derivative according to any one of the above [1] to [6] Or a prodrug thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein m is 0 or 1; [8] a condensed heterocyclic derivative of the above [7] or a precursor thereof or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, wherein m is 1, and ring A is a thiophene ring represented by the following formula; [9] The condensed heterocyclic derivative of any one of the above [1] to [8], or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein E ¹ is The condensed heterocyclic derivative of any one of the above [1] to [9], or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein E ² is an oxygen atom; allowed on the [11] as the above-mentioned [1] to [10] condensed heterocyclic derivative according to any one of, or a prodrug thereof, or a pharmacologically acceptable salt thereof or a hydrate of the compound vehicle Wherein, ring B is a benzene ring, a thiophene ring, or a pyridine ring; [12] a condensed heterocyclic derivative of the above [11] or a precursor thereof or a pharmacologically acceptable salt thereof or a hydrate or solvent thereof a compound wherein ring B is any one of the rings represented by the following formula; [13] The condensed heterocyclic derivative of the above [12], or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein n is 1 or 2 and has R on the ring. ^{B is} a ring represented by the ring B is any one of the following formulas; (wherein R ^B is synonymous with the above, in the case where R ^B is 2, two R ^B may be the same or different); [14] a condensed heterocyclic derivative such as the above [12] or [13] or a prodrug or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, wherein the ring B is any one of the rings represented by the following formula; [15] The condensed heterocyclic derivative of any one of the above [1] to [14], or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein R ^B is a halogen atom, a substitutable lower alkyl group, OW ⁴ (W ⁴ is a hydrogen atom or a substitutable lower alkyl group) or a cyano group; [16] a condensed heterocyclic derivative according to the above [15] or a precursor thereof or a pharmacological thereof a salt or a hydrate or a solvent thereof, wherein R ^B is a halogen atom, a lower alkyl group which may be substituted by a halogen atom, or OW ⁴ (W ⁴ is a hydrogen atom or a substitutable lower alkyl group) [17] The condensed heterocyclic derivative of the above [16], or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein R ^B is a fluorine atom, a chlorine atom, or OW W ⁴ is lower alkyl of ^4; allowed on the [18] as the above-mentioned [1] to [17] condensed heterocyclic derivative according to any one of, or a prodrug thereof, or a pharmacologically acceptable salt thereof a hydrate of Or a solvent, wherein U is a single bond, a methylene group or an ethyl group; [19] a condensed heterocyclic derivative according to any one of the above [1] to [18] or a precursor thereof or a pharmacological thereof Salt allowed or hydrated Or solvent thereof, wherein, X is -Y, -S-L-Y, -O-L-Y, -CO-L-Y, -SO 2 -L-Y, -S-Z or -O-Z The group shown (wherein L, Y, and Z are synonymous with the above); [20] The condensed heterocyclic derivative of the above [19] or a precursor thereof or a pharmacologically acceptable salt thereof or a hydrate thereof Or a solvent composition, wherein U is a single bond, and X is a group represented by -S-L-Y, -O-L-Y, -CO-L-Y or -SO ₂ -L-Y (wherein, [21] The condensed heterocyclic derivative of the above [19], or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein U is a sub Methyl, X is -Y (where Y is -NW ⁷ W ⁸ [W ⁷ and W ^{8 are} independently a hydrogen atom, a substitutable lower alkyl group, or Z (but not a hydrogen atom at the same time), W ⁷ and W ⁸ Alternatively, a nitrogen atom adjacent to the two may be substituted together to form a group which may be substituted with a cyclic amine group]), -S-Z or -O-Z (Z is synonymous with the above); [22] as described above [19] a condensed heterocyclic derivative or a precursor thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein U is an exoethyl group, X is -Y (wherein Y is Z, Z is synonymous with the above); [23] The condensed heterocyclic derivative of any one of the above [1] to [20] or a precursor thereof or pharmacologically acceptable thereof the salt or a hydrate of the compound or vehicle, where, L is C _{1 - 3} alkylene group; [24] as described [1] to [23] condensed heterocyclic derivative of any one or a prodrug Or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, wherein Z is a substitutable aryl group which may also be condensed; [25] a pharmaceutical composition comprising the above [1]~[24 a condensed heterocyclic derivative according to any one of the above, or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, as an active ingredient; [26] a pharmaceutical composition according to the above [25], a gonad-stimulating hormone releasing a hormone antagonist; [27] a pharmaceutical composition according to the above [25], a preventive or therapeutic agent for a hormonal-dependent disease, a reproductive modulator, a contraceptive, an ovulation inducing agent, or a sex hormone dependent Preventive agents for post-surgical cancer surgery; [28] The pharmaceutical composition of the above [27], sexual hormone-dependent diseases from the prostate hypertrophy, uterine fibroids, uterus Symptoms, uterine fibroids, early onset of adolescence, no menstrual disease, premenstrual syndrome, menstrual difficulties, polycystic ovarian syndrome, lupus erythematosus, hirsutism, dwarfism, sleep disorders, acne, alopecia, Az Diseases selected from the group consisting of Haimo, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, and pituitary tumors; and [29] pharmaceutical compositions as described in [25] above, Oral administration; and prevention or treatment of sexual hormonal-dependent diseases formed by administering an effective amount thereof, reproductive regulation methods, contraceptive methods, ovulation induction methods, or sex-related cancer after surgery Prevention method; such use for the manufacture of a pharmaceutical composition; release of a hormone agonist by a gonad-stimulating hormone, a chemotherapeutic agent, a gonadotropin-stimulated hormone-releasing hormone antagonist, 5α-reductase inhibition At least one agent selected from the group consisting of a group of agents, an adrenergic receptor inhibitor, an aromatase inhibitor, a para-adrenal androgen production inhibitor, and a hormone therapy agent a combination of pharmaceutical ingredients; and so on.

The condensed heterocyclic derivative (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof thereof, can regulate gonadotropin-stimulated hormone release due to superior GnRH antagonism The role of hormones to control the production and secretion of hormones and sex hormones, thereby using as a preventive or therapeutic agent for sexual hormone-dependent diseases.

The meanings of the terms used in this specification are as follows.

The "5-membered ring unsaturated hydrocarbon" means a hydrocarbon ring having a 5-membered ring of one or two double bonds.

"Heteroaryl" means a monocyclic heteroaryl group having one or more hetero atoms selected arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom (for example, thiazole, Oxazole, isothiazole, iso Oxazole, pyridine, pyrimidine, pyridyl ,despair , pyrrole, furan, thiophene, imidazole, pyrazole, Diazole, thiadiazole, triazole, tetrazole, furazan, etc.).

"Substitutable" means that it may have a substituent.

"5-membered ring heteroaryl" means a heterocyclic group of the above 5-membered monocyclic ring, and examples thereof include thiazole, Oxazole, isothiazole, iso Oxazole, pyrrole, furan, thiophene, imidazole, pyrazole, Diazole, thiadiazole, triazole, furoxan ring.

"Aryl" means phenyl.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"Lower alkyl" means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, pentyl, isopentyl, neopentyl, third A pentyl group, a hexyl group or the like having a carbon number of 1 to 6 which may also be branched.

"Lower alkenyl" means a carbon number of 2 to 6 such as a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group or a 2-methylallyl group. Alkenyl groups can also be branched.

The "lower alkynyl group" means an alkynyl group having a carbon number of 2 to 6 which may be branched, such as an ethynyl group or a 2-propynyl group.

The "lower alkylsulfonyl group" means a sulfonyl group substituted with the above lower alkyl group.

The "lower alkyl sulfinyl group" means a sulfinyl group substituted with the above lower alkyl group.

"Lower alkylene" means an alkylene group having a carbon number of 1 to 6 which may also be branched.

"C _{1 - 3} alkylene group" means a carbon number may also be branched alkylene of 1 to 3.

"Lower alkoxy" is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy, tert-butoxy, pentyloxy, iso Alkoxy groups having a carbon number of 1 to 6 which may be branched by a pentyloxy group, a neopentyloxy group, a third pentyloxy group, a hexyloxy group or the like.

"Lower alkoxycarbonyl" means an alkoxycarbonyl group having a carbon number of 2 to 7 which may also be branched.

"Lower alkyl sulphide" means an alkyl sulphide having a carbon number of 1 to 6 which may also be branched.

"Cycloalkyl" means a monocyclic cycloalkyl group having 3 to 8 carbon atoms (for example, a monocyclic naphthenic group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclodecyl group). base).

"Heterocycloalkyl" means a 3-8 membered ring heterocyclic ring having one or two or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 1 to 2 pendant oxy groups. Alkyl (eg pyrrolidinyl, piperidinyl, oxoperipyryl, Olinyl group, piperazine Oxyporide Base Alkyl group, azepanyl, dimercapto group, An oxazepanyl, thiazepanyl, acesulfame group, azocanyl, tetrahydrofuranyl, tetrahydropyranyl group, etc., in the case where a sulfur atom is present in the ring, Sulfur atoms can also be oxidized.

The "condensable ring" means that it may be condensed with one ring selected from the above cycloalkyl group, the above heterocycloalkyl group, the above aryl group, and the above heteroaryl group. Examples of the "cycloalkyl group which is condensed ring", "heterocycloalkyl group which is condensed ring", "aryl group which is condensed ring", and "heteroaryl group which is condensed ring" include, for example, fluorenyl group and isoindole. Mercapto, benzofuranyl, isobenzofuranyl, benzothienyl, benzo Azolyl, benzothiazolyl, benzopyrene Azyl, benzisothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, anthracene Phthalazinyl, quin Lolinyl, quinazolinyl, Cinnolinyl, 吲 Indolizinyl, Naphthyridinyl, Pteridinyl, Indanyl, Naphthyl, 1,2,3,4-tetrahydronaphthyl, porphyrin, Isoporphyrin , 2,3,4,5-tetrahydrobenzo[b] Oxepinyl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, For chromanyl, etc., valency can be paid by either ring.

The "cyclic amine group" means a group having at least one nitrogen atom in a heterocyclic alkyl group which may also be condensed, and having a bonding site in the ring, and examples thereof include a 1-pyrrolidinyl group and a 1-piperidyl group. Pyridyl, 1-piper Base, 4- Olinyl, 4-thia Boryl, 2,3,4,5,6,7-hexahydro-1H-indol-1-yl, 1-carbolinyl, 2-isoindolyl, 3,4-dihydro-1, 5-naphthyridin-1(2H)-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 3,4-dihydroquinolin-1(2H)-yl, 3,4-di Hydrogen isoquinoline-2(1H)-yl, octahydroquinoline-1(2H)-yl, octahydroisoquinoline-2(1H)-yl, perhydroquinoline, 2,3-dihydro-4H -1,4-Benzene 4-yl, 2,3-dihydro-4H-1,4-benzothiazide 4-yl, 3,4-dihydroquine Porphyrin-1(2H)-yl, 2,3-dihydro-4H-pyridinium [3,2-b][1,4] 4-yl, 2,3,4,5,-tetrahydro-1H-1-benzoindole-1-yl, 1,3,4,5-tetrahydro-2H-2-benzoindole-2- Base, 3,4-dihydro-1,5-benzo Indole-5(2H)-yl, 2,3-dihydro-4,1-benzothiazepin-1(5H)-yl, 3,4-dihydro-1,5-benzothiazepine-5 ( 2H)-yl, 2,3-dihydro-4,1-benzothiazepine-1(5H)-yl, 2,3,4,5-tetrahydro-1H-1,5-benzodioxan- 1-yl, 2,3,4,5-tetrahydro-1H-1,4-benzodioxin-1-yl, 5,6,7,8-tetrahydro-4H-thiophene [3,2-b呯-4-yl, 3,4,5,6-tetrahydro-1-benzoxazole -1 (2H)-yl group and the like.

"(2) Lower alkylamino group" means an amine group which is mono- or disubstituted with the above lower alkyl group, and the two lower alkyl groups which are disubstituted may be different, and the two lower alkyl groups may be combined with the two. Adjacent nitrogen atoms together form a cyclic amine group.

"(2) Lower alkylamine-methyl indenyl" means an aminomethyl group which is mono- or disubstituted with the above lower alkyl group, and the two lower alkyl groups which are disubstituted may be different, and two lower alkyl groups may also be used. The nitrogen atoms adjacent to the two together form a cyclic amine group.

"醯基" means an aliphatic carboxylic acid fluorenyl group, a cycloalkyl carboxylic acid fluorenyl group, a heterocycloalkyl carboxylic acid fluorenyl group, an aryl carboxylic acid fluorenyl group, a heteroaryl group having a carbon number of 2 to 7. A carboxylic acid thiol group.

"Nylideneamino group" means an amine group substituted with the above fluorenyl group.

In the general formula (I), the ring A is preferably a 5-membered ring heteroaryl group, more preferably a thienyl group, and particularly preferably a thiophene ring represented by the following formula.

R ^{A is} preferably a halogen atom, a substitutable lower alkyl group, COOW ¹ or CONW ² W ³ (W ¹ to W ^{3 are} independently a hydrogen atom or a substitutable lower alkyl group, and W ² and W ³ may be used as both The adjacent nitrogen atom is combined to form a substitutable cyclic amine group or the like, and more preferably a lower alkyl group, a carboxyl group or an amine formazan group which is substituted with a group selected from a hydroxyl group and a carboxyl group and an aminomethyl group. Good is a carboxyl group. In the case where m is 2 or more, the plural R ^A may be the same or different. m is preferably 0 or 1, and in the case where m is 1, the ring A having R ^A in the ring is particularly preferably a thiophene ring represented by the following formula.

In this case, R ^{A is more} preferably a substitutable lower alkyl group, COOW ¹ or CONW ² W ³ (W ¹ to W ^{3 are} independently a hydrogen atom or a substitutable lower alkyl group, and W ² and W ³ may be used together with both. The substituted nitrogen atom is combined with the adjacent nitrogen atom to form a substitutable cyclic amine group).

In the general formula (I), as E ¹ , an oxygen atom is preferred. As E ² , an oxygen atom is preferred.

In the general formula (I), as the ring B, a benzene ring, a thiophene ring or a pyridine ring is preferred, and a benzene ring or a thiophene ring is more preferred. In this case, the bonding position of the ring B is preferably as shown in the following formula:

Very good for the following: (wherein, the bond hand on the left side indicates the bond with N of the condensed pyrimidine ring, and the bond hand on the right side indicates the bond with U.)

In the case where n is 1 or 2, the ring B having R ^B on the ring is preferably of the following formula: (wherein, the bond of R ^B is not bonded in the hands, the bond on the left side represents the bond with the N of the condensed pyrimidine ring, and the bond on the right represents the bond of the U bond) Thiophene ring or pyridine ring. R ^{B is} preferably a halogen atom, a substitutable lower alkyl group, OW ⁴ (W ⁴ is a hydrogen atom or a substitutable lower alkyl group), a cyano group or the like, and more preferably a halogen atom or a halogen atom. The alkyl group, OW ⁴ , particularly preferably a fluorine atom, a chlorine atom, and W ⁴ is a lower alkyl group OW ⁴ . In the case where n is 2, the plural R ^Bs may be the same or different. Furthermore, the ring B having R ^{B on} the ring is of the following formula (wherein, the bond of either of R ^{B 1} and R ^{B 2} is not bonded, the bond on the left side represents the bond with the N of the condensed pyrimidine ring, and the bond on the right side represents the bond with the U In the case of a benzene ring, a thiophene ring or a pyridine ring represented by a bond, R ^{B 1 is} preferably a fluorine atom or a chlorine atom, and R ^{B 2 is} preferably a fluorine atom, a methoxy group or an ethoxy group. More preferably, it is a methoxy group.

In the general formula (I), U is preferably a single bond, a methylene group or an extended ethyl group.

In particular, in the following various cases, the blood dynamics are good, and it is preferable: (i) in the case where U is a single bond, as X-s-L-Y, -O-L-Y, - a group represented by CO-L-Y or -SO ₂ -L-Y (wherein L is a substitutable lower alkyl group; Y is Z or -NW ⁷ W ⁸ [W ⁷ and W ^{8 are} independently hydrogen atoms) And may be substituted for lower alkyl or Z (but not hydrogen atom at the same time), or W ⁷ and W ⁸ may form a group substituted with a cyclic amino group together with a nitrogen atom adjacent to the two; Z is a condensed ring which may be substituted with a cycloalkyl group, a condensed ring which may be substituted with a heterocycloalkyl group, a condensed ring which may be substituted with an aryl group, or a condensed ring which may be substituted with a heteroaryl group; (ii) In the case where U is a methylene group, X is a Y-form (wherein Y is -NW ⁷ W ⁸ [W ⁷ and W ^{8 are} independently a hydrogen atom, a lower alkyl group or a Z (but not a hydrogen atom at the same time, W) ^{7 is} preferably Z), or W ⁷ and W ⁸ may be combined with a nitrogen atom adjacent to the two to form a group which may be substituted with a cyclic amine group]), -S-Z or -O-Z; Iii) In the case where U is an ethyl group, X is -Y (wherein Y is Z, Z is synonymous with the above).

As L, a C _{1 - 3} lower alkylene group is more preferable.

As Z, a substitutable heteroaryl group which may also be a condensed ring or a substitutable aryl group which may also be a condensed ring is preferred, and a substituted aryl group which may also be a condensed ring is more preferred. Among Z, a substituent which may be possessed as a substitutable heteroaryl group or a substitutable aryl group is preferably a halogen atom, a substitutable lower alkyl group, or a substitutable lower alkoxy group, more preferably a halogen atom. A lower alkyl group which may be substituted with a halogen atom or a lower alkoxy group or a hydroxyl group, or a lower alkoxy group which may be substituted with a halogen atom or a lower alkoxy group or a hydroxyl group.

Examples of the substituent which may be substituted with a cyclic amino group, a substituted cycloalkyl group or a substituted heterocycloalkyl group include a pendant oxy group, a halogen atom, a cyano group, a hydroxyl group, and a substitutable lower alkyl group. , cycloalkyl, substitutable lower alkoxy, substitutable lower alkylthio, carboxy, substitutable lower alkoxycarboxy, amine mercapto, (b) lower alkoxyamine, mercapto, substituted aryl , aryloxy, heteroaryl, heteroaryloxy, decylamino, and the like, which may be the same or different complex substitutions. Among them, in R ^A , a substituent which may be possessed as a substitutable cyclic amino group formed by NW ² W ³ excludes an aryl group-containing group.

Examples of the substituent which the substitutable aryl group or the substituted heteroaryl group may have include a halogen atom, a nitro group, a cyano group, a hydroxyl group, a substitutable lower alkyl group, a cycloalkyl group, a substitutable lower alkoxy group, and the like. Substitutable lower alkylthio, carboxy, substitutable lower alkoxycarboxy, amine mercapto, (b) lower alkylamine, aryl, aryloxy, heteroaryl, heteroaryloxy And mercaptoamine groups, etc., these groups may also be substituted by the same or different complex numbers.

The above substituent may be substituted with a cycloalkyl group, a condensed ring-substituted heterocycloalkyl group, a condensed ring-substituted aryl group, and a condensed ring-substituted heteroaryl group. It may also be replaced by the same or different complex rings of the condensed ring.

In the case where Z is a substitutable cycloalkyl group which may also be condensed or may be substituted with a heterocycloalkyl group, the substituent which may be possessed as such a group is preferably a substitutable aryl group or a heteroaryl group. base.

As a substitutable lower alkyl group, a substitutable lower alkyl group, a substitutable lower alkenyl group, a substitutable lower alkynyl group, a substitutable lower alkyl sulfonyl group, a substitutable lower alkyl sulfinyl group, a substitutable lower alkoxy group The substituent which may be substituted by a lower alkylthio group or a lower alkoxycarbonyl group may, for example, be a halogen atom, a cyano group, a hydroxyl group, a lower alkoxy group, a lower alkylthio group or an amine group, a) a lower alkylamino group, a carboxyl group, a lower alkoxycarbonyl group, an amine carbenyl group, a (di) lower alkylamine formamyl group, an aryl group, a heteroaryl group, etc., and these groups may be the same or different Multiple substitution. Wherein, in R ^A , an aryl group-containing group and a heteroaryl group-containing group are excluded.

An example of a method for producing a condensed heterocyclic derivative represented by the general formula (I) in the present invention is shown below.

[Method 1]

In the condensed heterocyclic derivative represented by the general formula (I) of the present invention, a compound wherein E ¹ is an oxygen atom can be produced, for example, by the method of Process 1.

Wherein R ¹ is a nitro group or a lower alkoxycarbonyl group, and ring A, ring B, R ^A , R ^B , m, n, E ² , U, and X are synonymous with the above.

(Step 1-1) In an inert solvent (for example, tetrahydrofuran, dichloromethane, a mixed solvent thereof, etc.), a reagent such as phosgene, diphosgene or triphosgene is used in a base (for example, triethylamine, N, In the presence of N-diisopropylethylamine, pyridine, etc., the amine compound ( 1 ) can be converted to the isocyanate compound ( 2 ) by treatment at a temperature of from ice-cold to reflux for 30 minutes to 1 day.

(Step 1-2) in an inert solvent (e.g., tetrahydrofuran, dichloromethane, etc.) in a base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylamino) The isocyanate compound ( 2 ) and the amine compound ( 3 ) are reacted in an ice-cold-reflux temperature for 1 hour to 3 days in the presence or absence of pyridine, etc., whereby the urea compound ( 4 ) or the present invention can be produced. A condensed heterocyclic derivative (Ia).

(Step 1-3) in an inert solvent (e.g., tetrahydrofuran, dichloromethane, methanol, ethanol, N,N-dimethylformamide, water, etc.) in a base (e.g., triethylamine, N, N-) Urea compound ( 4 ) in the presence or absence of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium hydride, sodium hydroxide, etc. The condensed heterocyclic derivative (Ia) of the present invention can be produced by reacting for 5 minutes to 3 days under ice-cold temperature.

[Method 2]

In the condensed heterocyclic derivative represented by the general formula (I) of the present invention, a compound wherein E ² is an oxygen atom can be produced, for example, by the method of Process 2.

Ring A, ring B, R ^A , R ^B , m, n, U, and X in the formula are synonymous with the above.

(Step 2-1) The guanamine compound ( 6 ) can be produced by condensing the carboxylic acid compound ( 5 ) with the amine compound ( 3 ) by a general chlorination method or a condensing agent method. The chlorinated acid method can be used, for example, in an inert solvent (dichloromethane, 1,2-dichloroethane, toluene), using a reagent such as sulfinium chloride or oxalic acid chloride in an additive such as N, N-dimethyl The carboxylic acid compound ( 5 ) is treated in an ice-cold-reflux temperature for 30 minutes to 1 day in the presence or absence of a carbamide or the like, thereby being used as a chlorinated acid in an inert solvent (for example, In pyridine, dichloromethane, tetrahydrofuran, water, etc., in a base (triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydrogencarbonate In the presence or absence of the amine compound ( 3 ), it is reacted for 1 hour to 3 days at a temperature of usually cold-reflux. The condensing agent system can be used, for example, in an inert solvent (N,N-dimethylformamide, dichloromethane, tetrahydrofuran) using a condensing agent (1-ethyl-3-(3-dimethylaminopropyl) ) carbodiimide hydrochloride, dicyclohexylcarbodiimide, etc. in the presence of an additive (1-hydroxybenzotriazole, etc.) in a base (triethylamine, N, N-diiso) In the presence or absence of propylethylamine, pyridine, 4-dimethylaminopyridine, etc., the carboxylic acid compound ( 5 ) and the amine compound ( 3 ) are reacted at room temperature to reflux temperature. Hours ~ 3 days.

(Step 2-2) The nitro amine compound (6), the contacting being carried out by the general reduction method of reducing a metal hydrogen complex compound or a reduction method, etc. can be manufactured amine compound (7). The contact reduction method can be carried out, for example, in an inert solvent (methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, etc.) using a catalyst (palladium carbon powder or the like) to cause the guanamine compound ( 6 ) to be generally at room temperature to reflux. At temperature, treat for 1 hour to 3 days. The metal hydrogen complex reduction method can be used, for example, in an inert solvent (methanol, ethanol, tetrahydrofuran, etc.) using a reducing agent (sodium borohydride or the like) in the presence of an additive (nickel (II) bromide or the like) to give a guanamine. Compound ( 6 ) is treated for 30 minutes to 1 day at room temperature generally at room temperature.

(Step 2-3) In an inert solvent (for example, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, etc.), phosgene, diphosgene, triphosgene, 1,1'-carbonyldi- a reagent such as 1H-imidazole, in the presence or absence of a base (for example, triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydride, etc.), The amine compound ( 7 ) is treated at a temperature of from ice-cold to reflux for 30 minutes to 1 day, whereby the condensed heterocyclic derivative (Ib) of the present invention can be produced.

(Step 2-4) In an inert solvent (tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol), using a reagent such as carbon disulfide in a base (triethylamine, N,N-diisopropyl In the presence of ethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, etc., the amine compound ( 7 ) is treated at a temperature of from ice-cold to reflux for 1 hour to 3 days, whereby the condensed impurities of the present invention can be produced. Ring derivative (Ic).

(Step 2-5) In an inert solvent (tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, etc.), a reagent such as diphenylcyanocarbamate (carbonimidate) is used in the base ( The amine compound ( 7 ) is treated in an ice-cold-reflux temperature for 1 hour in the presence of triethylamine, N,N-diisopropylethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, and the like. The condensed heterocyclic derivative (Id) of the present invention can be produced by ~3 days.

[Method 3]

The amine compound ( 3 ) used as a raw material compound in the above Process 1 or 2 can be, for example, a commercially available product or a nitro compound ( 8 ) synthesized by a method described in the literature or a combination of a general synthesis method or the like. It is obtained by reduction by a general reduction method or the like. For example, it can be produced by the method of the following Process 3.

The ring B, R ^B , n, U, and X in the formula are synonymous with the above.

(Step 3) The amine compound ( 3 ) can be produced by reduction of a nitro group ( 8 ) nitro group by a general contact reduction method or a metal hydrogen complex reduction method. The contact reduction method can be used, for example, in an inert solvent (methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, etc.), using a catalyst (palladium carbon powder, ruthenium carbon powder, platinum carbon powder, etc.) to make a nitro compound. ( 8 ) It is treated for 1 hour to 3 days at room temperature to reflux temperature. The metal hydrogen complex reduction method can be carried out, for example, in an inert solvent (methanol, ethanol, tetrahydrofuran, etc.) using a reducing agent (sodium borohydride or the like) in the presence of an additive (nickel (II) bromide or the like) to form a nitro group. The compound ( 8 ) is treated for 30 minutes to 1 day in an ice-cold room temperature.

Further, in the case where the compound used in the above production method or the compound formed varies depending on the reaction conditions or has a functional group which hinders the progress of the reaction, it is of course possible to protect it with a suitable protecting group conventionally used by a practitioner, and suitably The stage is removed.

The condensed heterocyclic derivative represented by the general formula (I) of the present invention can be converted into a precursor of a carboxyl group, a hydroxyl group and/or an amine group by reacting a procatalyst reagent by a usual method. Further, the prodrug of the condensed heterocyclic derivative represented by the general formula (I) of the present invention may be described in pp. 163-198 (Guangchuan Bookstore) of the molecular design of the "Development of Pharmaceutical Products", Volume 7. Under physiological conditions, it is converted to the compound (I) of the present invention.

The condensed heterocyclic derivative represented by the general formula (I) or a precursor thereof can be used as a pharmacologically acceptable salt by a usual method. Examples of such a salt include inorganic acid salts such as hydrochloric acid and nitric acid; organic acid salts such as acetic acid and methanesulfonic acid; and sodium and potassium salts; N,N'-dibenzylethylenediamine and 2-amine. An addition salt of an organic base such as ethanol.

The condensed heterocyclic derivative represented by the general formula (I) or a precursor thereof may be obtained in the form of a hydrate or a solvent during the purification or salt formation thereof. The pharmaceutical composition of the present invention may be any one of a fused heterocyclic derivative or a precursor thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof.

Further, regarding the condensed heterocyclic derivative represented by the general formula (I) or a precursor thereof, there are also cases in which tautomers, geometric isomers and/or optical isomers are present, and the pharmaceutical composition of the present invention Any one of them may be used, and a mixture thereof may also be used.

The condensed heterocyclic derivative (I) of the present invention has superior GnRH antagonism, can regulate the action of the glandular hormone to stimulate the release of hormones, and control the production and secretion of hormones and sex hormones. Therefore, the condensed heterocyclic derivative (I) of the present invention or a precursor thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof thereof can be extremely useful as, for example, prostatic hypertrophy, uterine fibroids, Endometriosis, uterine fibroids, early onset of adolescence, no menstrual disease, premenstrual syndrome, menstrual difficulties, polycystic ovarian syndrome, lupus erythematosus, hirsutism, dwarfism, sleep disorders, acne, alopecia , Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, and pituitary tumors. Prevention or treatment of sexual hormone-dependent diseases, reproductive regulators, birth control pills, An ovulation-inducing agent, or a prophylactic agent for post-operative treatment of sex hormone-dependent cancer.

The condensed heterocyclic derivative (I) of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, may be mixed with a conventional preparation carrier to prepare a pharmaceutical composition. .

The preparation carrier may be appropriately used in combination with the administration form described later, and examples thereof include an excipient such as lactose; a lubricant such as magnesium stearate; a disintegrant such as carboxymethylcellulose; and a hydroxypropyl group; a binder such as methyl cellulose; a surfactant such as macrogol; a foaming agent such as sodium hydrogencarbonate; a dissolution aid such as cyclodextrin; a sour agent such as citric acid; A stabilizer for sodium or the like; a pH adjuster such as phosphate.

The administration form of the pharmaceutical composition of the present invention may, for example, be an oral administration agent such as a powder, a granule, a fine granule, a dry syrup, a tablet or a capsule; an injection, a tablet, an elixir or the like. Non-oral administration agents, etc.; oral administration agents are preferred.

The compound of the general formula (I) of the present invention or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, is preferably produced in the following manner: Adults are administered orally every day. The agent is administered in the range of 0.1 to 1000 mg, and the injection is administered in the range of 0.01 to 100 mg.

Further, the pharmaceutical composition of the present invention may further contain other pharmaceutical agents. As such an agent, for example, a GnRH agonist (for example, Leuprorelin Acetate, Gonadorelin, Buserelin, Triptorelin, Goserelin, Nafarelin, Histrelin, Deslorelin, Meterelin, Lecirelin, etc. Chemotherapeutic agents (eg, Ifosfamide, Adriamycin, Peplomycin, Cisplatin, Cyclophosphamide, 5-FU, UFT, A Methotrexate, Mitomycin C, Mitoxantron, Paclitaxel, Dotaxel, etc., peptide GnRH antagonists (eg, cetrix) (Cetrorelix), Canary (Ganirelix), Abari (Abarelix), Ozar (Ozarelix), Izre (Iturelix), De Garry (Degarelix), Teveri (Teverelix), etc., 5 alpha-reductase inhibitors (eg, Finasteride, Dutasteride, etc.), alpha adrenergic receptor inhibitors (eg, stansulo (Tamsulosin), Slodo (Silodosin), Urapidil, etc., aromatase inhibitors (for example, Fadrozole, Letrozole, Anastrozole, Formestane, etc.), deputy Adrenal androgen production inhibitors (eg, Liarozole, etc.), and hormonal therapies (eg, anti-alrading agents (Tamoxifen, Fulvestrant, etc.), corpus luteum Hormone (Medroxyprogesterone, etc.), male, emollient, anti-androgen (Oxendolone, Flutamide, Nilutamide, ratio) Bicalutamide, etc.), etc.

(Example)

The present invention will be described in more detail by way of the following examples and test examples, but the invention is not limited thereto.

(Reference example 1)

2-Chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)aniline in 1,2,3,4-tetrahydroquinoline (3.12g) and sodium bicarbonate (2.66) A solution of water (60 mL) and 4-chloro-3-nitrobenzenesulfonium chloride (5.4 g) in tetrahydrofuran (30 mL) was added to EtOAc EtOAc m. The reaction mixture was diluted with ethyl acetate, washed with water, 1 mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-[(4-chloro-3-nitrophenyl)sulfonyl]-1,2,3,4-tetrahydroquinoline (5.0 g). This was dissolved in tetrahydrofuran (45 mL), and methanol (45 mL), nickel (II) bromide (0.15 g) and sodium borohydride (1.61 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, then at room temperature Stir for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3/1) to give the title compound (4.33 g).

(Reference examples 2 to 11)

Using the corresponding starting materials, the compounds of Reference Examples 2 to 11 described in Tables 1 to 2 were obtained in the same manner as in Reference Example 1.

(Reference example 12)

Dichloro-5-(3,4-dihydroquinolin-1(2H)-ylmethyl)aniline in 4-chloro-3-nitrobenzyl alcohol (1 g) in dichloromethane (10 mL) To the solution were added triethylamine (1.21 mL) and methanesulfonyl chloride (0.5 mL), and stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give methanesulfonic acid (4-chloro-3-nitrobenzyl) (1.08 g). This was dissolved in acetonitrile (4 mL)-ethanol (4 mL), and 1,2,3,4-tetrahydroquinoline (1.62 g) and a solvent amount of sodium iodide were added thereto, and the mixture was stirred at 60 ° C overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3 / 1) to give 1-(4-chloro-3). -Nitrobenzyl)-1,2,3,4-tetrahydroquinoline (1.22 g). This was dissolved in tetrahydrofuran (12 mL), and methanol (12 mL), nickel (II) bromide (44 mg) and sodium borohydride (0.46 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, followed by stirring at room temperature. 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3/1) to give the title compound (0.79 g).

(Reference Example 13)

4-Benzyloxy-6-chloroaniline 4-chloro-3-nitrobenzene (0.13g) was dissolved in N,N-dimethylformamide (3mL), potassium carbonate (0.31g) The benzyl bromide (0.14 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL), and methanol (3 mL), nickel (II) bromide (8 mg) and sodium borohydride (85 mg) were added under ice cooling, and stirred at the same temperature 30 After a minute, it was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (0.15 g).

(Reference examples 14 to 17)

Using the corresponding starting materials, the compounds of Reference Examples 14 to 17 shown in Table 2 were obtained in the same manner as in Reference Example 13.

(Reference Example 18)

3-(2-Phenylethyl)aniline 3-bromonitrobenzene (1 g), styrene (1.7 mL), palladium (II) acetate (95 mg), ginseng (2-methylphenyl)phosphine ( A mixture of 0.3 g) and N,N-diisopropylamine (5 mL) was heated to reflux for 24 hours. The reaction mixture was diluted with diethyl ether, washed with 1 mol/L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1) to give 3-((E)-2 -Phenylvinyl)nitrobenzene (0.76 g). Add 10% palladium carbon powder (50 mg) to a solution of 3-((E)-2-phenylvinyl)nitrobenzene (0.26 g) in methanol (10 mL) at room temperature under hydrogen atmosphere Stir for 2 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g).

(Reference Example 19)

N,N-dimethyl group of diethyl 2-aminothiophene-3,4-dicarboxylate in sulfur (6.9 g), ethyl pyruvate (25 g) and ethyl cyanoacetate (24.4 g) Triethylamine (21.8 g) was added to a mixture of decylamine (130 mL) at room temperature over 30 min and the reaction mixture was stirred at 50 ° C for 2 hr. Water (1 L) and saturated brine (50 mL) were added to the mixture, and the mixture was extracted three times with diethyl ether (250 mL). The extract was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography (eluent solvent: diethyl ether) to give the title compound (28.2 g).

(Reference Example 20)

1-(2-Fluoro-6-methoxyphenyl)ethanol was added to a solution of 2-fluoro-6-methoxybenzaldehyde (0.5 g) in tetrahydrofuran (10 mL). 1.15 mol/L diethyl ether solution, 3.4 mL), stirred at the same temperature for 1 hour, followed by stirring at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with diethyl ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.45 g).

(Reference example 21)

2-Fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenylamine in 4-fluoro-3-nitrobenzene (synthesized according to the method described in International Publication WO97/39064) Add azodicarboxylate at room temperature in a solution of 0.2 g), 1-(2-fluoro-6-methoxyphenoxy)ethanol (0.22 g) and triphenylphosphine (0.4 g) in tetrahydrofuran (1.5 mL) Diisopropyl acid (40% in toluene, 0.84 mL) was stirred at room temperature for 2 hours. The reaction mixture was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 8/1) to give 2-fluoro- 5-[1-(2-Fluoro-6-methoxyphenyl)ethoxy]-1-nitrobenzene (0.15 g). This was dissolved in tetrahydrofuran (3 mL), and methanol (3 mL), nickel (II) bromide (5 mg) and sodium borohydride (55 mg) were added under ice cooling, and stirred at the same temperature for 30 minutes, followed by stirring at room temperature 30 minute. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3 / 1) to give the title compound (0.11 g).

(Reference examples 22 to 29)

Using the corresponding starting materials, the compounds of Reference Examples 22 to 29 shown in Tables 3 to 4 were obtained in the same manner as in Reference Example 13 or Reference Example 21.

(Reference Example 30)

1-[4-Fluoro-3-(t-butoxycarbonylamino)phenyl]-2-methyl-1-propane was added to concentrated sulfuric acid (10 mL) at -20 ° C. 2-methyl-1-propane (2.92 g) was stirred at the same temperature for 15 minutes. A mixture of fuming nitric acid (1.4 mL) and concentrated sulfuric acid (4.2 mL) was added at -20 ° C and stirred at the same temperature for 20 min. Ice (100 g) was added to the reaction mixture, and the mixture was warmed to room temperature with stirring. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water (3 times), saturated aqueous sodium hydrogencarbonate (2 times), and brine, and dried over anhydrous sodium sulfate. Distilled under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 95/5 to 85/15) to give 1-(4-fluoro-3-nitrophenyl) )-2-methyl-1-propane (1.8 g). This was dissolved in ethanol (5 mL), and 10% palladium carbon powder (0.36 g) was added thereto, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 90/10 to 83/17) to give 1-(3-amino-4-fluorophenyl). )-2-methyl-1-propane (1.45 g). This was dissolved in tetrahydrofuran (33 mL), and 4-dimethylaminopyridine (0.29 g) and di(t-butyl)dicarbonate (3.49 g) were added, and the mixture was refluxed for 1.5 hr. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 95/5) to give 1-{4-fluoro-3-[N,N- Bis(t-butoxycarbonyl)amino]phenyl}-2-methyl-1-propane (1.8 g). This was dissolved in methanol (15 mL), potassium carbonate (1.96 g) was added, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was cooled to room temperature, and water and brine were added, and ethyl acetate was evaporated. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 5 / 1) to give the title compound (1.14 g).

(Reference example 31)

1-(3-Amino-4-fluorophenyl)-2-(5-fluoro-2-methoxyphenyl)-2-methyl-1-propane 1-[4-fluoro-3-( Third butoxycarbonylamino)phenyl]-2-methyl-1-propane (0.11 g), 2-bromo-4-fluoroanisole (0.057 mL), palladium(II) acetate (4.5 mg) A mixture of tris(tert-butyl)phosphine tetrafluoroborate (5.8 mg) and sodium tributoxide (96 mg) in tetrahydrofuran (1 mL) was stirred at 70 ° C for 3 days under argon. After stirring with water for 10 minutes in the reaction mixture, the mixture was poured into 1 mol/L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1) to give 1-[4-fluoro-3-(t-butoxycarbonylamine) Phenyl]-2-(5-fluoro-2-methoxyphenyl)-2-methyl-1-propane (45 mg). This was dissolved in hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL) and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by an aminopropyl sulfonium chloride column chromatography (eluent solvent: n-hexane / ethyl acetate = 4/1 to 3/1) to give the title compound (25 mg).

(Reference examples 32 to 35)

Using the corresponding starting materials, the compounds of Reference Examples 32 to 35 shown in Tables 4 to 5 were obtained in the same manner as in Reference Example 31.

(Reference Example 36)

1-(1-Phenylethylthio)aniline 1-methoxyethyl was added to a mixture of 3-mercaptoaniline (1 g) and potassium carbonate (1.21 g) in N,N-dimethylformamide (20 mL) Bromine (1.2 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 1 / 1) to give the title compound (1.78 g).

(Reference Example 37)

Using the corresponding starting material, the compound of Reference Example 37 shown in Table 5 was obtained in the same manner as in Reference Example 36.

(Reference Example 38)

Add 3-nitrothiophenol (0.5g) to a mixed solution of 3-(1-methyl-1-phenylethylthio)aniline in water (1.6mL)-concentrated sulfuric acid (1.6mL), stir at room temperature 1 hour. A solution of α-methylstyrene (0.38 g) in tetrahydrofuran (1.6 mL) was added to the mixture and stirred at room temperature for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 3/2) to give 3-(1-methyl-1-phenylethyl). Sulfur) nitrobenzene (0.88 g). This was dissolved in tetrahydrofuran (10 mL), and methanol (10 mL), nickel (II) bromide (35 mg) and sodium borohydride (0.37 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, followed by stirring at room temperature. 1 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to give the title compound (0.69 g). ).

(Reference Example 39)

3-Amino-4-fluoro-N-methyl-N-phenylbenzamide was added to a solution of 4-fluoro-3-nitrobenzoic acid (2 g) in dichloromethane (50 mL). Methylformamide (0.01 mL) and grass chloroform (6.86 g) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran (10 mL) was added to a mixture of N-methylaniline (1.22 g) and sodium hydrogencarbonate (2.72 g) in THF (20 mL). The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-fluoro-3-nitro-N-methyl -N-Phenylbenzamide (2.95 g). This was dissolved in tetrahydrofuran (50 mL), and methanol (50 mL), nickel (II) bromide (0.12 g) and sodium borohydride (1.26 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, then at room temperature Stir for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (2.33 g).

(Reference Example 40)

Using the corresponding starting material, the compound of Reference Example 40 shown in Table 5 was obtained in the same manner as in Reference Example 39.

(Reference examples 41 to 42)

Using the corresponding starting materials, the compounds of Reference Examples 41 to 42 shown in Table 5 were obtained in the same manner as in Reference Example 21.

(Reference example 43)

4-fluoro-2-methoxy-5-nitrobenzenesulfonium chloride 3-N-fluoro-4-nitrobenzene (2.56 g), potassium carbonate (4.5 g) and methyl iodide (4.63 g) The mixture of N-dimethylformamide (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into water and washed with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3-fluoro-4-nitroanisole (2.56 g). This was dissolved in 1,2-dichloroethane (13 mL), and chlorosulfonic acid (1.3 mL) was added under ice cooling, and the mixture was refluxed for 4 hr. The reaction mixture was diluted with methylene chloride, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 2 / 1) to give the title compound (0.51 g).

(Reference examples 44 to 69)

Using the corresponding starting materials, the compounds of Reference Examples 44 to 69 shown in Tables 6 to 9 were obtained in the same manner as in Reference Example 1.

(Reference example 70)

4-Amino-5-methylthiophene-2,3-dicarboxylic acid dimethyl hydrochloride was added to sodium (0.38 g) in methanol (15 mL) under ice cooling, and stirred at the same temperature until sodium was dissolved. Ethyl 2-mercaptopropionate (1.81 g) and dimethyl crotonate (2.17 g) were added to the reaction mixture, and the mixture was heated to reflux for 3 hr. After the reaction mixture was cooled to room temperature, water (100 mL) was added and washed with diethyl ether. The aqueous layer was ice-cooled, made acidic by adding 2 mol/L hydrochloric acid, and extracted twice with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 4/1 to 3/1) to give 5-methyl-4- oxo-2. 3-bismethoxycarbonyltetrahydrothiophene (2.68 g). This was dissolved in methanol (8 mL), hydroxyammonium chloride (0.92 g) was added, and the mixture was refluxed for 2 hr. After the reaction mixture was cooled to room temperature, ethyl acetate (24 mL) was added and stirred for 10 min. The precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (0.77 g).

(Reference examples 71~72)

Using the corresponding starting materials, the compounds of Reference Examples 71 to 72 shown in Table 9 were obtained in the same manner as in Reference Example 30.

(Reference examples 73 to 77)

Using the corresponding starting materials, the compounds of Reference Examples 73 to 77 shown in Tables 9 to 10 were obtained in the same manner as in Reference Example 31.

(Reference Example 78)

4-bromo-2-(t-butoxycarbonylamino)-1-fluorobenzene in 1-bromo-4-fluoro-3-nitrobenzene (1.56 g), nickel (II) bromide (78 mg), A mixture of methanol (28 mL) and tetrahydrofuran (28 mL) was added to sodium borohydride (805 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes, and stirred at room temperature for 30 minutes, and then the reaction mixture was poured into saturated sodium hydrogencarbonate. In an aqueous solution, extraction was carried out with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-fluoroaniline (1.3 g). This was dissolved in tetrahydrofuran (30 mL), and 4-dimethylaminopyridine (0.26 g) and di(t-butyl)dicarbonate (3.1 g) were added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Methanol (21 mL) and potassium carbonate (2.94 g) were added to the residue, and the mixture was refluxed for 2 hr. After water was added to the reaction mixture, it was poured into a saturated saline solution and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 95/5) to give the title compound (1.72 g).

(Reference Example 79)

2-(3-Amino-4-fluorophenyl)-1-(2-methoxyphenyl)-2-methyl-1-propane 1-(2-methoxyphenyl)-2- Methyl-1-propane (0.58g), 4-bromo-2-(t-butoxycarbonylamino)-1-fluorobenzene (0.94g), palladium acetate (II) (37mg), tetrafluoroborate A mixture of (t-butyl)phosphine (47 mg) and sodium tributoxide (0.78 g) in tetrahydrofuran (10 mL) was stirred overnight at 60 ° C under argon. After adding water to the reaction mixture and stirring for 10 minutes, the mixture was poured into 1 mol/L hydrochloric acid, and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 95/5 to 85/15) to give 2-[3-(t-butoxycarbonylamine) 4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propane (0.91 g). 2-[3-(Tertibutoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propane (0.34 g) obtained Hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.22 g).

(Reference Example 80~81)

Using the corresponding starting materials, the compounds of Reference Examples 80 to 81 shown in Table 10 were obtained in the same manner as in Reference Example 79.

(Reference Example 82)

Substituting benzene for 4-fluoro-3-nitrobenzene and replacing 4-(2-fluoro-6-methoxyphenyl)ethanol with 4-chloro-3-nitrobenzyl alcohol, as in Reference Example 21 The compound of Reference Example 82 shown in Table 11 was obtained.

(Reference Example 83)

2-Chloro-5-(2-phenylethyl)aniline in 4-chloro-3-nitrobenzaldehyde (1 g) and benzyltriphenylphosphonium bromide (2.34 g) in toluene (35 mL) suspension Sodium hydride (55%, 0.28 g) was added and stirred at room temperature overnight. 1 mol/L hydrochloric acid was added to the reaction mixture, and extraction was carried out with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1) to give 2-chloro-5-((Z)-2-phenylvinyl )-1-nitrobenzene (0.79 g). The obtained 2-chloro-5-((Z)-2-phenylvinyl)-1-nitrobenzene (0.16 g) was dissolved in ethanol (6 mL)-methanol (2 mL), and 5% 铑 powder was added. End (20mg) and The porphyrin (5 mg) was stirred at room temperature overnight under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 5 / 1) to give the title compound (87 mg).

(Reference Example 84)

1-(Tertibutoxycarbonylamino)-5-ethynyl-2-fluorobenzene 4-bromo-2-(t-butoxycarbonylamino)-1-fluorobenzene (0.57 g), three a mixture of methyl decyl acetylene (0.55 mL), hydrazine (triphenylphosphine) palladium (0) (23 mg) and copper (I) iodide (7 mg) in N,N-diisopropylamine (5.7 mL). Stir at 80 ° C overnight. After cooling the reaction mixture to room temperature, it was diluted with diethyl ether. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 15 / 1) to give 1-(t-butoxycarbonylamino)-2-fluoro- 5-trimethyldecyl ethynylbenzene (0.6 g). This was dissolved in tetrahydrofuran (10 mL), and tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 2.4 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 20/1 to 10/1) to give the title compound ( 0.34g).

(Reference Example 85)

2-Bromo-3,4-difluoroanisole was added to a solution of 3,4-difluoroanisole (2 mL) in tetrahydrofuran (50 mL), and n-butoxy lithium (2.67 mol/L hexane) was added at -78 °C. The alkane solution, 6.95 mL) was stirred at the same temperature for 30 minutes. Bromine (1.04 mL) was added to the reaction mixture, stirred at -78 °C for 15 min and stirred for 1 hour under ice cold. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 9/1) to give the title compound (0.91 g).

(Reference Example 86)

2-fluoro-5-(2-phenylethyl)aniline 1-(t-butoxycarbonylamino)-5-ethynyl-2-fluorobenzene (0.11 g), iodobenzene (0.1 g), A mixture of bis(triphenylphosphine)palladium(0) (16 mg) and copper (I) iodide (5 mg) in N,N-diisopropylamine (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1) to give 1-(t-butoxycarbonylamino)-2-fluoro- 5-Phenylethynylbenzene (0.14 g). This was dissolved in ethyl acetate (3 mL), and 10% palladium carbon powder (50 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 1-(t-butoxycarbonylamino)-2-fluoro-5-(2-phenylethyl)benzene (0.11 g). This was dissolved in hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 8/1 to 5/1) to give the title compound (53 mg).

(Reference Example 87~99)

Using the corresponding starting materials, the compounds of Reference Examples 87 to 99 shown in Tables 11 to 13 were obtained in the same manner as in Reference Example 86.

(Reference example 100)

2-fluoro-4-methoxy-5-(2-phenylethyl)aniline 2-bromo-5-fluoro-4-nitroanisole (0.46 g), phenylacetylene (67 mg), hydrazine A mixture of (triphenylphosphine)palladium(0) (38 mg) and copper (I) iodide (13 mg) in N,N-diisopropylamine (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1 to 5/1) to give 5-fluoro-4-nitro-2-phenyl. Ethylanisole (0.18 g). This was dissolved in ethyl acetate (5 mL), and 10% palladium carbon powder (0.45 g) was added thereto, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 10/1 to 4/1) to give the title compound (87 mg).

(Reference Example 101)

2-fluoro-5-[2-(2-methoxyphenyl)-1,1-dimethylethyl]aniline in 2-[3-(t-butoxycarbonylamino)-4-fluoro Add borohydride sodium (0.17 g) to a mixture of phenyl]-1-(2-methoxyphenyl)-2-methyl-1-propane (0.59 g) in tetrahydrofuran (7.5 mL)-water (0.75 mL). ), stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 4 / 1) to give 2-[3-(t-butoxycarbonylamino)-4. -Fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propane (0.54 g). This was dissolved in ethanol (8 mL)-tetrahydrofuran (3 mL), and 2 mol/L hydrochloric acid (0.2 mL) and 10% palladium carbon powder (0.27 g) were added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. Sodium hydrogencarbonate was added to the reaction mixture, and after stirring for 10 minutes, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 7/1) to give 2-[3-(t-butoxycarbonylamino)-4. -Fluorophenyl]-1-(2-methoxyphenyl)-2-methoxypropane (0.15 g). Hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (0.11 g).

(Reference example 102)

4-Chloro-3-nitrothiophenol 4-Chloro-3-nitroaniline (5.18 g) was added to concentrated sulfuric acid (30 mL) under ice-cooling, and stirred at the same temperature for 5 min. Add a solution of sodium nitrite (3.1 g) in water (30 mL) to the mixture under ice-cooling, warm to 50 ° C, and add potassium disulfate 0-ethyl (14.4 g) in water (60 mL) at 50 ° C Stir for 1 hour. The reaction mixture was cooled to room temperature and extracted twice with diethyl ether. The extracts were combined, washed with 1 mol/L sodium hydroxide aqueous solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, and the residue was applied to a cerium oxide gel tube. Column chromatography (extraction solvent: n-hexane ~ n-hexane / ethyl acetate = 7 / 3) was purified to give O-ethyl S-(4-chloro-3-nitrophenyl) disulfate (2.96 g). This was dissolved in tetrahydrofuran (50 mL), and added to a suspension of lithium aluminum hydride (1.62 g) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was ice-cooled, and water (1.8 mL), 15% aqueous sodium hydroxide (1. After the insoluble matter was filtered off, the filtrate was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid, water and brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane/ethyl acetate = 9/1 to 1/9) to give the title compound (1.28 g).

(Reference Example 103)

5-Benzylthio-2-chloroaniline in a solution of 4-chloro-3-nitrothiophenol (0.4g) and benzyl bromide (0.3mL) in N,N-dimethylformamide (6mL) Potassium carbonate (0.44 g) was added and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 9/1) to give 1-benzylthio-4-chloro-3-nitro Benzene (0.54 g). This was dissolved in methanol (5 mL)-tetrahydrofuran (5 mL), and then, under ice cooling, nickel (II) bromide (21 mg) and sodium borohydride (0.22 g) were added and stirred at the same temperature for 30 minutes and at room temperature. Stir under 1 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution and water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.38 g).

(Reference example 104)

2-Fluoro-5-mercaptoaniline in 5-bromo-2-fluoroaniline (4.15 g), methyl 3-mercaptopropionate (2.62 g), 4,5-bis(diphenylphosphino)-9,9- Dimethyl (0.63g) and N,N-diisopropylethylamine (5.64g) of 1,4-two To the mixture of the alkane (80 mL), bis(dibenzylideneacetone)dipalladium(0) (0.3 g) was added, and the mixture was heated to reflux overnight under an argon atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 20/1 to 5/1 to 2/1) to give 2-fluoro-5-(2) -Methoxycarbonylethylthio)aniline (4.62 g). This was dissolved in tetrahydrofuran (120 mL), and potassium tributoxide (1 mol/L tetrahydrofuran solution, 80.6 mL) was added at -78 ° C, and stirred at the same temperature for 15 minutes. 1 mol/L hydrochloric acid (81 mL) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 5 minutes. The mixture was poured into ethyl acetate to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 4 / 1) to give the title compound (1.85 g).

(Reference example 105)

2-Fluoro-6-methoxybenzyl alcohol In a solution of 2-fluoro-6-methoxybenzaldehyde (0.63g) in tetrahydrofuran (5mL), water (0.5mL) and sodium borohydride (0.17g) Stir for 1 hour at room temperature. The reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure to give the title compound (0.58 g).

(Reference examples 106~107)

Using the corresponding starting materials, the compounds of Reference Examples 106 to 107 shown in Table 14 were obtained in the same manner as in Reference Example 105.

(Reference Example 108)

2-Fluoro-6-methoxybenzyl bromide in 2-ethyl-6-methoxybenzyl alcohol (0.78 g) and triethylamine (0.91 mL) in ethyl acetate (12 mL) Methanesulfonium chloride (0.43 mL) was stirred at the same temperature for 30 minutes. The insoluble material was filtered off, and the solution was washed with ethyl acetate (4 mL). Combine the filtrate and the washing solution, and add lithium bromide. 1 hydrate (2.62 g) was stirred at 55 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 7 / 3) to give the title compound (0.82 g).

(Reference examples 109~110)

Using the corresponding starting materials, the compounds of Reference Examples 109 to 110 shown in Table 14 were obtained in the same manner as in Reference Example 108.

(Reference Example 111)

Add 2-(5-fluoro-2-methoxyphenyl)-2-propanol 5-fluoro-2-methoxybenzaldehyde (1 g) in acetone (4 mL), add lithium permanganate at room temperature A solution of (1.54 g) in water (16 mL) was heated to reflux for 4 h. The reaction mixture was cooled to room temperature, and a 2 mol/L aqueous sodium hydroxide solution (5.2 mL) was added, and the insoluble matter was filtered out. After the filtrate was washed with ethyl acetate, 2 mol/L hydrochloric acid was added to the aqueous layer to make it acidic, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1 - ethyl acetate) to give 5-fluoro-2-methoxybenzoic acid (0.66). g). This was dissolved in N,N-dimethylformamide (15 mL), and lithium carbonate (0.63 g) and methyl iodide (0.26 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-fluoro-2-methoxybenzene. Methyl formate (0.7 g). This was dissolved in tetrahydrofuran (10 mL), and methyl magnesium iodide (3.0 mol/L diethyl ether solution, 3.82 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.65 g).

(Reference examples 112 to 113)

Using the corresponding starting materials, the compounds of Reference Examples 112 to 113 shown in Table 14 were obtained in the same manner as in Reference Example 111.

(Reference Example 114)

2-Fluoro-5-(2-fluorobenzylthio)aniline 2-fluoro-5-mercaptoaniline (0.13 g) and 2-fluorobenzyl bromide (0.12 mL) of N,N-dimethylformamide Potassium carbonate (0.25 g) was added to the solution of 5 mL), and stirred at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether, washed with water (2 times) and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 6 / 1) to give the title compound (0.17 g).

(Reference examples 115~126)

Using the corresponding starting materials, the compounds of Reference Examples 115 to 126 shown in Tables 15 to 16 were obtained in the same manner as in Reference Example 114.

(Reference example 127)

2-Fluoro-5-(1-methyl-1-phenylethylthio)aniline in a mixture of water (10 mL) and concentrated sulfuric acid (10 mL), sequentially added 2-fluoro-5-fluorenyl at room temperature A solution of aniline (1.85 g) and 2-phenyl-2-propanol (1.76 g) in tetrahydrofuran (10 mL) was stirred at room temperature for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogencarbonate solution and brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 6/1 to 3/1) to give the title compound (1.55 g).

(Reference examples 128~141)

Using the corresponding starting materials, the compounds of Reference Examples 128 to 141 shown in Tables 16 to 18 were obtained in the same manner as in Reference Example 127.

(Reference example 142)

4-fluoro-2-methoxy-5-nitrobenzene in a solution of 4-fluoro-2-methoxybenzene (1.42 g) and triethylamine (1.67 mL) in dichloromethane (20 mL) Ethyl chloroformate (1.05 mL) was added under ice cooling, and stirred at room temperature for 3 days. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Concentrated sulfuric acid (7 mL) was added to the residue under ice cooling, and stirred at the same temperature for 15 min. A mixture of fuming nitric acid (0.7 mL) and concentrated sulfuric acid (1 mL) was added dropwise under ice cooling, and stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the extract was washed with water (2 times) and brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 90/10 to 67/33) to give 2-ethoxycarbonyloxy-5-fluoro- 4-Nitroanisole (0.48 g). Methanol (8 mL) and sodium hydrogencarbonate (0.31 g) were added thereto, and stirred at room temperature for 42 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent (eluent solvent: n-hexane/ethyl acetate = 4/1), and filtered, and dried under reduced pressure to give the title compound (0.25 g).

(Reference example 143~147)

Using the corresponding starting materials, the compounds of Reference Examples 143 to 147 shown in Tables 18 to 19 were obtained in the same manner as in Reference Example 142.

(Reference Example 148)

2-ethoxy-4-fluoro-5-nitrobenzene in 4'-fluoro-2'-hydroxyacetophenone (3.08 g), cesium carbonate (13.0 g) and sodium iodide (0.6 g), To a suspension of N-dimethylformamide (20 mL), ethyl bromide (2.24 mL) was added and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To a residue and a solution of 4,4'-thiobis(6-tert-butyl-o-cresol) (39 mg) in dichloromethane (57.6 mL), 3-chloroperbenzoic acid (4.97 g) ), heating and refluxing overnight. The reaction mixture was ice-cooled, a 10% aqueous sodium sulfite solution was added and stirred for 20 min. The organic layer was separated, washed with water (3 times), saturated aqueous sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was dissolved in methanol (10 mL)-THF (20 mL). The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-ethoxy-4-fluorobenzene (3.0 g). The title compound was obtained by the same method as that of Reference Example 142, using this, instead of 4-fluoro-2-methoxybenzene.

(Reference example 149)

Using the corresponding starting material, the compound of Reference Example 149 shown in Table 19 was obtained in the same manner as in Reference Example 20.

(Reference example 150)

2-[2-(T-butoxydimethyldimethylalkyloxy)ethoxy]benzyl alcohol in 2-hydroxybenzyl alcohol (0.4g) and potassium carbonate (0.67g) N,N-dimethyl To a suspension of carbamide (6 mL), 2-(t-butyldimethylsilyloxy)ethyl bromide (1.05 mL) was added and stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether, washed with water, a 1 mol/L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 5 / 1) to give the title compound (0.32 g).

(Reference example 151)

Using the corresponding starting material, the compound of Reference Example 151 described in Table 19 was obtained in the same manner as in Reference Example 150.

(Reference example 152)

N,N-dimethylformamide (30 mL) of 2-(t-butoxy dimethyl decyloxymethyl)benzyl alcohol in 1,2-benzenedimethanol (2 g) and imidazole (1.13 g) To the solution, third butoxy dimethyl chlorodecane (2.08 g) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to give the title compound ( 1.46 g).

(Reference examples 153 to 154)

Using the corresponding starting materials, the compounds of Reference Examples 153 to 154 shown in Table 20 were obtained in the same manner as in Reference Example 152.

(Reference example 155)

2,3-Difluoro-6-(2-methoxyethoxy)benzyl alcohol in N,N of 2,3-difluoro-6-hydroxybenzylcarbaldehyde (0.63 g) and potassium carbonate (0.83 g) To a suspension of dimethylformamide (4 mL), 2-methoxyethyl bromide (0.45 mL) was added and stirred at room temperature for 3 days. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (extraction solvent: n-hexane / ethyl acetate = 85/15 to 60/40) to obtain 2,3-difluoro-6-(2-A Oxyethoxyethoxy)benzylformaldehyde (0.62 g). This was dissolved in tetrahydrofuran (6 mL), and water (0.6 mL) and sodium borohydride (0.12 g) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.61 g).

(Reference example 156~159)

Using the corresponding starting materials, the compounds of Reference Examples 156 to 159 shown in Table 20 were obtained in the same manner as in Reference Example 155.

(Reference example 160)

1-(2,3-Difluoro-6-methoxyphenyl)-1-cyclobutanol in 3,4-difluoroanisole (2.47 g) in tetrahydrofuran (50 mL) at -78 ° C n-Butyllithium (2.64 mol/L n-hexane solution, 6.5 mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. A solution of cyclobutane (1 g) in tetrahydrofuran (20 mL) was added and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 5 / 1) to give the title compound (2.69 g).

(Reference example 161)

2-Chloro-5-(1-methyl-1-phenylethoxy)aniline 4-chloro-3-nitrobenzene (0.5g), tri(n-butyl)phosphine (0.72mL) and 2-benzene In a solution of benzyl-2-propanol (0.26 g) in tetrahydrofuran (5 mL), 1,1'-azobis(N,N-dimethylformamide) (0.5 g) was added and stirred at 60 ° C 20 hour. The reaction mixture was diluted with diethyl ether and the insoluble material was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 10/1) to give 2-chloro-5. -(1-Methyl-1-phenylethoxy)-1-nitrobenzene (0.19 g). This was dissolved in tetrahydrofuran (3.5 mL), and methanol (3.5 mL), nickel (II) bromide (11 mg) and sodium borohydride (0.12 g) were added under ice cooling, and stirred at the same temperature for 30 minutes, followed by room Stir for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3/1) to give the title compound (0.14 g).

(Reference examples 162~166)

Using the corresponding starting materials, the compounds of Reference Examples 162 to 166 shown in Table 21 were obtained in the same manner as in Reference Example 161.

(Reference examples 167~308)

Using the corresponding starting materials, the compounds of Reference Examples 167 to 308 shown in Tables 22 to 41 were obtained in the same manner as in Reference Example 13 or Reference Example 21.

(Reference Example 309)

4-cyano-2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)phenylamine using 4-bromo-2-fluoro-5-(2,3-difluoro-6 -Methoxybenzyloxy)aniline substituted 5-bromo-2-fluoroaniline, 4-bromo-2-fluoro-5-(2,3-difluoro-6-A was synthesized in the same manner as in Reference Example 78 Oxybenzyloxy)-1-(tritoxycarbonylamino)benzene. A mixture of this compound (0.24 g) and copper (I) (90 mg) N-methyl-2-pyrrolidone (1 mL) was stirred at an external temperature of 220 ° C for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 2 / 1 to 1 / 1) to give the title compound (54 mg).

(Reference Example 310)

4-fluoro-3-(2,3-difluoro-6-methoxybenzyloxy)phenylamine 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methyl A suspension of oxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL), and methanol (3 mL), water (3 mL) and lithium hydroxide were added. 1 hydrate (0.5 g) was stirred at room temperature for 1 hour. 1 mol/L hydrochloric acid (15 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent (hexane/ethyl acetate = 4/1) and filtered, and dried under reduced pressure to give 4-fluoro-3-(2,3-difluoro-6-methoxy (Benzyloxy)benzoic acid (0.31 g). Dissolve this in 1,4-two Triethylamine (0.41 mL) and diphenylphosphoniumamine (0.21 mL) were added to aq. (4 mL), and stirred at room temperature for 1 hour and heated to reflux for 4 hours. A 1 mol/L aqueous sodium hydroxide solution (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane/ethyl acetate = 2/1 to 1/1), and then dichloromethane was added to the crude product to remove insolubles. The solvent of the filtrate was distilled off under reduced pressure to give the title compound (70 mg).

(Reference examples 311~321)

Using the corresponding starting material, the compounds of Reference Examples 311-321 described in Tables 41 to 43 were obtained in the same manner as in Reference Example 13 or Reference Example 21.

(Reference Example 322)

The compound of Reference Example 322 shown in Table 43 was obtained by the same method as Reference Example 160 using the corresponding starting material.

(Reference examples 323~324)

Using the corresponding starting materials, the compounds of Reference Examples 323 to 324 shown in Table 43 were obtained in the same manner as in Reference Example 161.

(Reference example 325)

Add 2-chloroperbenzene to a solution of 2,3-difluoro-6-methoxybenzene in 2,3-dichloro-6-methoxybenzaldehyde (2.58 g) in dichloromethane (45 mL) Formic acid (5.97 g) was heated to reflux overnight. The reaction mixture was ice-cooled, a 10% aqueous sodium sulfite solution was added and stirred for 20 min. The organic layer was separated, washed with water (2 times), a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL)-methanol (7.5 mL). The reaction mixture was poured into 1 mol/L hydrochloric acid and diluted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was sequentially subjected to cerium oxide gel column chromatography (eluent solvent: n-hexane to n-hexane/ethyl acetate = 2/3) and aminopropyl cerium oxide gel column chromatography ( The elution solvent: ethyl acetate/methanol = 9/1 to 3/2) was purified to give the title compound (1.7 g).

(Reference Example 326)

Using the corresponding starting material, the compound of Reference Example 326 described in Table 43 was obtained in the same manner as in Reference Example 325.

(Reference Example 327)

2,4-Difluoro-5-nitrobenzyl alcohol was added to a solution of 2,4-difluorobenzaldehyde (2.27 g) in dichloromethane (6 mL). To the mixture was added fuming nitric acid (1 mL) under ice-cooling, and stirred at the same temperature for 30 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, water was added and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution (2 times), water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane to n-hexane/ethyl acetate = 7/3) to obtain 2,4-difluoro-5-nitrobenzaldehyde ( 2.63g). The obtained 2,4-difluoro-5-nitrobenzaldehyde (1 g) was dissolved in tetrahydrofuran (15 mL), and sodium borohydride (0.3 g) was added under ice cooling, and the mixture was stirred at room temperature for 5 minutes. 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.76 g).

(Reference Example 328)

The compound of Reference Example 328 shown in Table 43 was obtained by the same method as Reference Example 327 using the corresponding starting material.

(Reference examples 329~331)

Use 2,3-difluoro-6-methoxybenzene or 2,3-difluoro-6-(2-methoxyethoxy)benzene instead of 4-fluoro-3-nitrobenzene and use 4- Instead of 1-(2-fluoro), fluoro-3-nitrobenzyl alcohol or 2,4-difluoro-5-nitrobenzyl alcohol or 4-fluoro-2-methoxy-5-nitrobenzyl alcohol -6-methoxyphenyl)ethanol The compound of Reference Examples 329 to 331 shown in Table 44 was obtained by the same method as that of Reference Example 21.

(Reference Example 332)

N,N-dimethylformamide of 2,3-difluoro-6-(2-methoxyethoxy)aniline in 3,4-difluorobenzene (1.43 g) and cesium carbonate (4.89 g) 2-Methoxyethyl bromide (0.94 mL) was added to a suspension (10 mL), and stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with a 1 mol/L sodium hydroxide aqueous solution, water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (39 mL), and n-butyl lithium (2.64 mol/L n-hexane solution, 3.25 mL) was added at -78 ° C, and the mixture was stirred at the same temperature for 30 minutes. Dry ice (10 g) was added to the reaction mixture, and stirred at room temperature for 30 min. 2 mol/L hydrochloric acid was added to the reaction mixture to make it acidic, and extraction was carried out with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid. (1.48g). The obtained 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (0.5 g) was dissolved in 1,4-two Acetone (10 mL) was added with triethylamine (0.45 mL) and diphenylphosphoniumamine (0.61 mL), and stirred at room temperature overnight. Ethanol (0.99 g) was added to the reaction mixture, and the mixture was heated to reflux for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A 5 mol/L aqueous sodium hydroxide solution (4.3 mL) was added to a suspension of the residue in ethanol (10 mL), and the mixture was refluxed for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water (2 times) and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3 / 1) to give the title compound (75 mg).

(Reference Example 333)

Using the corresponding starting material, the compound of Reference Example 333 shown in Table 44 was obtained in the same manner as in Reference Example 332.

(Reference Example 334)

2-fluoro-5-[N-(2,6-difluorophenyl)-N-methylamino]methyl-4-methoxyaniline in 4-fluoro-2-methoxy-5-nitrate To a solution of the benzyl alcohol (0.3 g) in dichloromethane (5 mL), triethylamine (0.31 mL) and methanesulfonium chloride (0.14 mL) were added at room temperature and stirred for 3 hours. The reaction mixture was diluted with methylene chloride, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in acetonitrile (2 mL)-ethanol (2 mL), and the mixture of sodium iodide and 2,6-difluoroaniline (0.45 mL) was added and stirred at 60 ° C overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 2/3) to give 5-fluoro-2-[N-(2,6- Difluorophenyl)amino]methyl-4-nitroanisole (0.41 g). This was dissolved in N,N-dimethylformamide (3 mL), and sodium hydride (55%, &lt Methyl iodide (0.096 mL) was added to the reaction mixture and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane-hexane/ethyl acetate = 1/1) to give 5-fluoro-2-[N-(2,6- Difluorophenyl)-N-methylamino]methyl-4-nitroanisole (0.17 g). This was dissolved in methanol (3 mL)-tetrahydrofuran (3 mL). Toluene (II) (5 mg) and sodium borohydride (52 mg) were added and the mixture was stirred at room temperature for 15 minutes and stirred at room temperature. 15 minutes. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution and water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane to n-hexane / ethyl acetate = 3/2) to give the title compound (0.12 g).

(Reference Example 335)

Using the corresponding starting material, the compound of Reference Example 335 shown in Table 44 was obtained by the same method as Reference Example 334.

(Reference example 336)

2-Fluoro-5-[N-(2-fluoro-6-methoxyphenyl)-N-methylamino]methylaniline in 4-fluoro-3-nitrobenzoic acid (1.57 g) N,N-dimethylformamide (0.005 mL) and grass chloroform (4.32 g) were added to a solution of chloromethane (25 mL), and the mixture was stirred at room temperature for 1 hr. A solution of the residue in tetrahydrofuran (5 mL) was added to a suspension of 2-fluoro-6-methoxyaniline (1.2 g) and sodium hydrogencarbonate (2.14 g) in tetrahydrofuran (10 mL) and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane and filtered, and dried under reduced pressure to give 4-fluoro-3-nitro-N-(2-fluoro-6-methoxyphenyl) benzamide ( 1.1g). This was dissolved in N,N-dimethylformamide (12 mL), and sodium hydride (55%, EtOAc) The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water (3 times) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-fluoro-3-nitro-N-(2-fluoro -6-Methoxyphenyl)-N-methylbenzamide (1.15 g). The obtained 4-fluoro-3-nitro-N-(2-fluoro-6-methoxyphenyl)-N-methylbenzamide (0.3 g) was dissolved in methanol (10 mL)-tetrahydrofuran (10 mL) Under ice cooling, nickel (II) bromide (10 mg) and sodium borohydride (0.11 g) were added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3-amino-4-fluoro-N-(2-fluoro-6- Methoxyphenyl)-N-methylbenzamide (0.27 g). This was dissolved in tetrahydrofuran (8 mL) and borane was added. Tetrahydrofuran complex (1 mol/L tetrahydrofuran solution, 3.3 mL) was heated under reflux for 2 hours. Methanol was added to the reaction mixture under ice cooling and stirred for 10 minutes. The mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 3/1) to give the title compound (0.11 g).

(Reference examples 337~340)

Using the corresponding starting materials, the compounds of Reference Examples 337 to 340 shown in Table 45 were obtained in the same manner as in Reference Example 336.

(Reference examples 341~342)

Using the corresponding starting materials, the compounds of Reference Examples 341 to 342 shown in Table 45 were obtained in the same manner as in Reference Example 325.

(Reference examples 343~344)

Use 2,3-difluoro-6-(2-ethoxyethoxy)benzene or 2,3-difluoro-6-[2-(t-butyldimethylmethylalkyloxy)ethoxy Benzene instead of 4-fluoro-3-nitrobenzene, 4-fluoro-3-nitrobenzyl alcohol instead of 1-(2-fluoro-6-methoxyphenyl)ethanol, according to Reference Example 21 In the same manner, the compounds of Reference Examples 343 to 344 shown in Table 45 were obtained.

(Reference example 345)

4-Fluoro-3-nitro-2-methoxybenzoic acid To a solution of 4-fluoro-2-methoxybenzoic acid (0.96 g) was added concentrated sulfuric acid (6 mL) and stirred for 15 min. Concentrated sulfuric acid (0.6 mL) was added to the mixture under ice cooling, and stirred at the same temperature for one hour. Ice was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes and then extracted with ethyl acetate. The extract was washed with water (2 times) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A mixed solvent (n-hexane/ethyl acetate = 2/1) was added to the residue, and the insoluble material was filtered, and dried under reduced pressure to give the title compound (0.78 g).

(Reference example 346)

Using the corresponding starting material, the compound of Reference Example 346 shown in Table 46 was obtained in the same manner as in Reference Example 336.

(Example 1)

5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2 , 4(1H,3H)-dione was suspended in tetrahydrofuran (10 mL) of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.5 g) and triethylamine (0.84 mL). A solution of triphosgene (0.41 g) in tetrahydrofuran (5 mL) was added to the mixture and stirred at 60 ° C for one hour. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL), and 2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)aniline (0.64 g) and 4-dimethylamino group were added. A solution of pyridine (0.49 g) in tetrahydrofuran (8 mL) was stirred at 60 ° C for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (15 mL). Sodium methoxide (28% methanol solution, 1.15 mL) was added to this solution and stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.65 g).

(Examples 2 to 21)

Using the corresponding starting materials, the compounds of Examples 2 to 21 shown in Tables 47 to 49 were obtained in the same manner as in Example 1. Here, in the case of Example 6, ethanol was used instead of methanol, and sodium oxyacetate was used instead of sodium methoxide.

(Example 22)

5-carboxy-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2,4 ( 1H,3H)-dione in 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3 , 4-d]pyrimidine-2,4(1H,3H)-dione (0.2g) in methanol (12mL) - tetrahydrofuran (4mL) solution was added lithium hydroxide. 1 hydrate (0.16 g) was stirred at 60 ° C overnight. 1 mol/L hydrochloric acid was added to the reaction mixture, and the crystals which precipitated were collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.18 g).

(Examples 23 to 29)

Using the corresponding starting materials, the compounds of Examples 23 to 29 shown in Tables 50 to 51 were obtained in the same manner as in Example 1 and Example 22.

(Embodiment 30)

5-Aminomethylmercapto-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2 , 4(1H,3H)-dione in 5-carboxy-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3 ,1,4-'-carbonylbis-1H-imidazole (9 mg) was added to a solution of 4-pyrimidine-2,4(1H,3H)-dione (14 mg) in tetrahydrofuran (1 mL). hour. To the reaction mixture was added 28% aqueous ammonia (0.5 mL), and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: methylene chloride / methanol = 10/1) to give the title compound (13 mg).

(Example 31)

5-methylamine-mercapto-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine -2,4(1H,3H)-dione The target compound was obtained by the same method as Example 30 using the corresponding raw material.

(Example 32)

5-(1-hydroxy-1-methylethyl)-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3 ,4-d]pyrimidine-2,4(1H,3H)-dione in 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)- Add methyl magnesium iodide (Isopropyl) phenyl] thiophene [3,4-d] pyrimidine-2,4(1H,3H)-dione (0.1 g) in tetrahydrofuran (10 mL) 3 mol/L diethyl ether solution, 0.19 mL), and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (85 mg).

(Example 33)

5-hydroxymethyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2, 4(1H,3H)-dione in 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene A solution of [3,4-d]pyrimidine-2,4(1H,3H)-dione (0.2 g) in tetrahydrofuran (4 mL) was added with diisobutylaluminum hydride (1.01 mol/L in toluene) under ice cooling. 1.5 mL) and stirred for 1 hour. Ethyl acetate was added to the reaction mixture and stirred for 10 minutes, then 1 mol/L hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (0.11 g).

(Example 34)

5-Mercapto-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2, 4(1H,3H)-dione in 5-hydroxymethyl-3-[2-chloro-5-(3,4-dihydroxyquinolin-1(2H)-ylsulfonyl)phenyl]thiophene [ Manganese (IV) (0.77 g) was added to a solution of 3,4-d]pyrimidine-2,4(1H,3H)-dione (77 mg) in N,N-dimethylformamide (2.1 mL). Stir at room temperature overnight. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered. The filtrate was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (32 mg).

(Example 35)

5-methoxycarbonyl-3-{2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenyl}thiophene [3,4-d]pyrimidine-2 , 4(1H,3H)-dione was added to a mixture of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (90 mg) and triethylamine (0.15 mL) in tetrahydrofuran (3 mL) A solution of triphosgene (74 mg) in tetrahydrofuran (3 mL) was stirred at 60 ° C for 30 min. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL) and added to 2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenylamine (0.1 g) and 4-dimethoxyamine A solution of the pyridine (88 mg) in tetrahydrofuran (3 mL) was stirred at 60 ° C overnight. 1 mol/L hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in methanol (5 mL). Sodium methoxide (28% methanol solution, 0.21 mL) was added to this solution and stirred at room temperature for 15 min. 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/2) to give the title compound (0.14 g).

(Examples 36 to 47)

Using the corresponding starting materials, the compounds of Examples 36 to 47 shown in Tables 52 to 53 were obtained in the same manner as in Example 35.

(Example 48)

5-carboxy-3-{2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenyl}thiophene [3,4-d]pyrimidine-2,4 ( 1H,3H)-dione in 5-methoxycarbonyl-3-{2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)ethoxy]phenyl}thiophene [3 Add lithium hydroxide to a mixture of 4-d]pyrimidine-2,4(1H,3H)-dione (0.12g) and methanol (3mL). 1 hydrate (99 mg) was stirred at 50 ° C for 1 hour. To the reaction mixture, 1 mol/L hydrochloric acid was added to make it acidic, and the crystals which precipitated were collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.11 g).

(Examples 49 to 60)

Using the corresponding starting materials, the compounds of Examples 49 to 60 shown in Tables 53 to 55 were obtained in the same manner as in Example 48.

(Examples 61 to 65)

Using the corresponding starting materials, the compounds of Examples 61 to 65 shown in Table 55 were obtained in the same manner as in Example 35.

(Examples 66 to 70)

Using the corresponding starting materials, the compounds of Examples 66 to 70 shown in Tables 55 to 56 were obtained in the same manner as in Example 48 or Example 93.

(Example 71)

The compound of Example 71 shown in Table 56 was obtained by the same method as Example 35 using the corresponding material.

(Example 72)

5-methoxycarbonyl-3-[3-(1-phenylethylsulfinyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione in 5 -methoxycarbonyl-3-[3-(1-phenylethylsulfanyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (50 mg) in acetone (50 mg) Sodium hydrogencarbonate (24 mg) and OXONE (registered trademark) (84 mg) were added to a solution of water (0.6 mL), and stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1 mol/L hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in methanol, filtered, and dried under reduced pressure to give the title compound (45 mg).

(Example 73)

5-methoxycarbonyl-3-[3-(1-phenylethylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione at 5- Methoxycarbonyl-3-[3-(1-phenylethylsulfanyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (50 mg) in acetone (3 mL) To the solution of water (0.6 mL), sodium hydrogencarbonate (77 mg) and OXONE (registered trademark) (0.28 g) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1 mol/L hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in methanol, filtered, and dried under reduced pressure to give the title compound (48 mg).

(Examples 74 to 76)

Using the corresponding starting materials, the compounds of Examples 74 to 76 shown in Tables 56 to 57 were obtained in the same manner as in Example 35.

(Example 77)

The compound of Example 77 shown in Table 57 was obtained by the same method as Example 73 using the corresponding material.

(Example 78)

The compound of Example 78 shown in Table 57 was obtained by the same method as Example 35 using the corresponding material.

(Examples 79 to 82)

Using the corresponding starting materials, the compounds of Examples 79 to 82 shown in Table 57 were obtained in the same manner as in Example 48.

(Example 83)

The compound of Example 83 shown in Table 58 was obtained in the same manner as in Example 73 and Example 48 using the corresponding material.

(Examples 84 to 87)

Using the corresponding starting materials, the compounds of Examples 84 to 87 shown in Table 58 were obtained in the same manner as in Example 48.

(Example 88)

The compound of Example 88 shown in Table 58 was obtained in the same manner as in Example 73 and Example 48 using the corresponding material.

(Examples 89 to 92)

Using the corresponding starting materials, the compounds of Examples 89 to 92 shown in Tables 58 to 59 were obtained in the same manner as in Example 35.

(Example 93)

5-carboxy-3-[2-fluoro-5-(N-methyl-N-phenylamine-methane)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)- Diketone in 5-methoxycarbonyl-3-[2-fluoro-5-(N-methyl-N-phenylaminecarbamimidyl)phenyl]thiophene [3,4-d]pyrimidine-2,4 (1H,3H)-dione (0.18g) and lithium hydroxide. A mixture of 1 hydrate (0.17 g) in THF (3 mL)-MeOH (3 mL) The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: methylene chloride / methanol = 8 / 1) to give the title compound (0.12 g).

(Example 94)

The compound of Example 94 shown in Table 59 was obtained by the same method as Example 35 and Example 93 using the corresponding raw material.

(Examples 95 to 97)

Using the corresponding starting materials, the compounds of Examples 95 to 97 shown in Table 59 were obtained in the same manner as in Example 93.

(Examples 98 to 100)

Using the corresponding starting materials, the compounds of Examples 98 to 100 shown in Tables 59 to 60 were obtained in the same manner as in Example 35.

(Examples 101 to 103)

Using the corresponding starting materials, the compounds of Examples 101 to 103 shown in Table 60 were obtained in the same manner as in Example 48.

(Examples 104 to 108)

Using the corresponding starting materials, the compounds of Examples 104 to 108 shown in Table 61 were obtained in the same manner as in Example 1.

(Examples 109 to 201)

Using the corresponding starting materials, the compounds of Examples 109 to 201 shown in Tables 61 to 74 were obtained in the same manner as in Example 1 and Example 48 or Example 93.

(Embodiment 202)

5-carboxy-3-[2-fluoro-5-(1-methyl-1-phenylethylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H) -Diketone will use 2-fluoro-5-(1-methyl-1-phenylethylthio)aniline instead of 2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl) Oxy]phenyl group, and 5-methoxycarbonyl-3-[2-fluoro-5-(1-methyl-1-phenylethylsulfanylphenyl) was obtained in the same manner as in Example 35. Thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (0.1g), dissolved in dichloromethane (2mL), 3-chloroperbenzoic acid (92mg) Stir under night. The reaction mixture was poured into water, and a 1 mol/L aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by cerium oxide gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/1 to 1/2) to give 5-methoxycarbonyl-3-[2-fluoro 5-(1-Methyl-1-phenylethylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (0.1 g). Using the obtained 5-methoxycarbonyl-3-[2-fluoro-5-(1-methyl-1-phenylethylsulfonyl)phenyl]thiophene [3,4-d]pyrimidine-2, 4(1H,3H)-dione substituted 5-methoxycarbonyl-3-[2-fluoro-5-(N-methyl-N-phenylaminecarbamimidyl)phenyl]thiophene [3,4- d] Pyrimidine-2,4(1H,3H)-dione, the title compound was obtained in the same manner as Example 93.

(Examples 203 to 232)

Using the corresponding starting materials, the compounds of Examples 203 to 232 shown in Tables 75 to 79 were obtained in the same manner as in Example 202.

(Example 233)

5-carboxy-3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]thiophene [3,4-d]pyrimidine- 2,4(1H,3H)-dione was suspended in tetrahydrofuran (5 mL) of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.13 g) and triethylamine (0.21 mL) In the turbid liquid, triphosgene (99 mg) was added under ice cooling, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL) and added to 2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.16 g) and 4- A solution of dimethylaminopyridine (0.12 g) in tetrahydrofuran (4 mL) was stirred at 60 ° C for 3 days. The reaction mixture was passed to ISO ROUTE SCX manufactured by IST Corporation, and eluted with ethyl acetate. After the eluate was concentrated under reduced pressure, the residue was dissolved in methanol (5 mL), and sodium sulfate (28% methanol solution, 0.29 mL) was added and the mixture was stirred at room temperature for 30 minutes. 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue and lithium hydroxide. A mixture of 1 hydrate (0.21 g) in tetrahydrofuran (4 mL)-MeOH (2 mL) The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/2 - ethyl acetate) to give the title compound (0.13 g).

(Examples 234 to 391)

Using the corresponding starting materials, the compounds of Examples 234 to 391 shown in Tables 79 to 102 were obtained in the same manner as in Example 233.

(Example 392)

The compound of Example 392 shown in Table 102 was obtained by the same method as Example 35 and Example 33 using the corresponding raw material.

(Examples 393 to 395)

Using the corresponding starting materials, the compounds of Examples 393 to 395 shown in Table 102 were obtained in the same manner as in Example 30.

(Example 396)

5-carboxy-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy]phenyl}thiophene [3,4-d]pyrimidine-2 , 4(1H,3H)-dione was suspended in tetrahydrofuran (5 mL) of 4-aminothiophene-2,3-dicarboxylic acid dimethyl hydrochloride (0.11 g) and triethylamine (0.19 mL) In the solution, triphosgene (84 mg) was added under ice cooling, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL) and added to 2-fluoro-5-{2,3-difluoro-6-[2-(t-butyldimethylmethylsulfanyloxy)ethoxy]benzyl A solution of oxy}aniline (0.17 g) and 4-dimethylaminopyridine (99 mg) in tetrahydrofuran (4 mL) was stirred at 60 ° C overnight. The reaction mixture was passed to ISO ROUTE SCX manufactured by IST Corporation, and eluted with ethyl acetate. After the eluate was concentrated under reduced pressure, the residue was dissolved in methanol (4 mL), and sodium sulfate (28% methanol solution, 0.23 mL) was added and the mixture was stirred at room temperature for 30 minutes. 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL), and tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 1.2 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue and lithium hydroxide. A mixture of 1 hydrate (0.17 g) in tetrahydrofuran (5 mL)-methanol (2.5 mL) 1 mol/L hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: ethyl acetate) to give the title compound (0.13 g).

(Examples 397-410)

Using the corresponding starting materials, the compounds of Examples 397 to 410 shown in Tables 102 to 104 were obtained in the same manner as in Example 396.

(Examples 411 to 416)

Using the corresponding starting materials, the compounds of Examples 411 to 416 shown in Tables 104 to 105 were obtained in the same manner as in Example 233.

(Example 417)

5-ethoxycarbonyl-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy]phenyl}thiophene [3,4-d] Pyrimidine-2,4(1H,3H)-dione in 5-carboxy-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy] Add p-toluenesulfonic acid to a suspension of phenyl}thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (0.65 g) in ethanol (10 mL)-tetrahydrofuran (5 mL). The hydrate (24 mg) was stirred overnight at an external temperature of 90 °C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/2 to 1/4) to give the title compound ( 0.39g).

(Example 418)

5-ethoxycarbonyloxy-3-(5-{6-[2-(ethoxycarbonyloxy)ethoxy]-2,3-difluorobenzyloxy}-2-fluorophenyl) Thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione in 5-ethoxycarbonyl-3-{2-fluoro-5-[2,3-difluoro-6-(2 -Hydroxyethoxy)benzyloxy]phenyl}thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione (80 mg) in ethyl acetate (2 mL) Pyridine (0.036 mL) and ethyl chloroformate (0.021 mL) were stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: n-hexane / ethyl acetate = 1/2) to give the title compound (38 mg).

(Example 419)

The compound of Example 419 shown in Table 106 was obtained by the same method as Example 418 using the corresponding material.

(Examples 420 to 426)

Using the corresponding starting materials, the compounds of Examples 420 to 426 shown in Tables 106 to 107 were obtained in the same manner as in Example 233.

(Example 427)

The compound of Example 427 shown in Table 107 was obtained by the same method as Example 396, using the corresponding material.

(Example 428)

The compound of Example 428 shown in Table 107 was obtained by the same method as Example 233 using the corresponding material.

The compound of Reference Example 1 to 346 of the chemical structure and ¹ H-NMR data are shown in Tables 1 to 46, the above-mentioned compound of Example 428 ~ 1 of chemical structure and ¹ H-NMR data are shown in Tables 47 ~ 107.

In the abbreviations in the table, Ref No. is a reference example number, Ex No. is an example number, Strc is a chemical structural formula, and Solv is a ¹ H-NMR measurement solvent.

[Test Example 1]

1) Selection of human GnRH receptor 1 (GnRHR1) and recombination of expression vector The cDNA from human pituitary gland (Bection Dikinson) was used as a template (templete), and human GnRHR1 (Accession No) reported by Kakar et al. The base arrangement of No. 45 to No. 1115 of .L03380) was amplified by a PCR method and inserted into a multiple selection site of pcDNA3.1 (+) (Invitrogen). The base sequence of the inserted DNA is identical to the reported base sequence.

2) Human GnRH receptor 1 is expressed in HEK293 (human fetal kidney) cells. It is prepared in HEK293 cells cultured (medium: MEM, 10% FCS, containing antibiotics, containing non-essential amino acids, containing pyruvate), using Lipofectamine 2000. (Invitrogen), a expression vector into which a human GnRHR1 gene was introduced was introduced by lipofection. After the introduction, the culture was carried out for 2 days and then used for the experiment.

3) Measurement of GnRH antagonistic effect The antagonism of the compound of human GnRHR1 was evaluated by the change of intracellular calcium concentration by GnRH stimulation. The culture medium of the HEK293 cell line transiently expressing GnRHR1 was washed with 200 μL of each buffer (Hanks' Balanced Salt Solutions, 20 mM N-2-hydroxyethylperidine). -N'-2-ethanesulfonic acid, 1.3 mM calcium chloride, 0.5 mM magnesium chloride, 0.4 mM magnesium sulfate) was washed once. 100 μL of a calcium ion-containing pigment solution (FLIPR Calcium Assay Kit, manufactured by Molecular Devices Co., Ltd.) was added thereto, and the mixture was cultured at 5% CO ₂ at 37 ° C for 1 hour. Thereafter, the intracellular calcium concentration was measured using FLEX STATION (manufactured by Molecular Devices Co., Ltd.) under the following conditions. Add 50 μL of the test substance diluted with buffer (washing buffer containing 0.1% calf serum albumin) to a chamber warmed to 37 ° C, and add 5 nM of GnRH 50 μ L after 1 minute. . So that intracellular calcium changes caused by GnRH stimulation of inhibitory concentration (IC _{5 0} value) of 50%, based by the chart (logit plot) was calculated (Table 108).

[Test Example 2] Oral Absorption Confirmation Test

1) Preparation of drug concentration measurement for tail vein administration SD mice that had been fasted for one night were used as experimental animals (CHARLES RIVER, male 7-week old, 170-210 g). 1 mg of the test compound was added in a ratio of 0.2 mL of N,N-dimethylacetamide, 0.798 mL of physiological saline, and 0.002 mL of 2N NaOH to prepare a 1.0 mg/mL solution. The body weight of the mice was measured, and the test compound was administered to the tail vein intravenously at an amount of 1 mL/kg (1 mg/kg) without anesthesia. The tail vein administration was carried out using a 26G injection needle and a 1 mL syringe. The blood collection time was set at 2, 15, 60, 120, 240, and 360 minutes after administration in the tail vein. The blood is centrifuged, and the plasma is used as a blood drug concentration measurement sample.

2) Preparation of drug concentration for oral administration The SD mice that had been fasted for one night were used as experimental animals (CHARLES RIVER, male 7-week old, 170-210 g). 3 mg of the test compound was added in a ratio of 0.2 mL of N,N-dimethylacetamide, 9.794 mL of 0.5% methylcellulose sodium solution, and 0.006 mL of 2N NaOH to prepare a solution of 0.3 mg/mL. Solution. The body weight of the mice was measured, and the test compound was orally administered at a dose of 10 mL/kg (3 mg/kg). Oral administration was carried out using a mouse doser (sonde) and a 2.5 mL syringe (syringe). The blood collection time was set at 15, 30, 60, 120, 240 and 360 minutes after administration in the tail vein. The blood is centrifuged, and the plasma is used as a blood drug concentration measurement sample.

3) Measurement of drug concentration In 0.025 mL of the plasma obtained by the above 1) and 2), 0.1 mL of an appropriate internal standard substance was added according to a usual method, and then 0.875 mL of acetonitrile was added to carry out deproteinization. After centrifugation, 0.005 mL of the supernatant was injected into LC-MS/MS. The blood drug concentration was determined by LC-MS/MS under the following conditions. Further, the detection line was added to 0.05 mL of blank plasma in an appropriate manner by appropriately adding an internal standard substance and various measurement target compounds, and the same procedure as above was carried out.

(LC) device: Agilent 1100 column: Cadenza C18 3 μ m 4.6 × 50 mm mobile phase: 10 mM aqueous ammonium acetate solution (pH 4.5) (A) / acetonitrile (B) (time and ratio of (A), (B) Shown in Table 109.) Column temperature: 40 ° C Flow rate: 0.5 mL / min

(MS/MS) device: API-4000 ionization method: ESI (Turbo Ion Spray)

Further, the bioavailability (%) is obtained by administering the blood concentration of the drug at each time obtained by the above method, using WinNonlin Professional manufactured by Pharsight Corporation, to obtain the tail vein intravenous administration and oral administration of the test compound. The area under the concentration-time curve is calculated according to the following formula.

Bioavailability (%) = { [(area in the blood concentration-time curve when administered orally) / 3] / (area in the blood concentration in the tail vein - the area under the time curve)} ×100

The maximum blood when administered orally in the concentration of the drug (a Cmax), bioavailability, 360 minutes after administration of blood drug concentration (C _{3 6 0)} are shown in Tables 110 to 112.

A: 1000ng/mL or more B: 300ng/mL~ less than 1000ng/mL

In Tables 110 to 112, the control compound 1 is the sulfonamide compound of Example 6 (4) described in Patent Document 2, and the control compound 2 is the sulfonamide compound of Example 31 described in Patent Document 2.

From the above results, the condensed heterocyclic derivative of the present invention is superior in blood dynamics (transition in blood, persistence) by oral administration as compared with the control compound. For example, the condensed heterocyclic derivatives of Examples 48, 146, 191, 202, 233, 367, 414, 420 are compared to the compound having a sulfonamide group of Example 22, and the amidino group of Example 95. The compound is more excellent in migration in blood, and is more suitable as a pharmaceutical composition for oral administration. Further, the condensed heterocyclic derivatives of Examples 146, 202, 233, 271, 367, 414, and 420 (more preferably, Examples 146, 233, 271, 367, and 414) are maintained as compared with the control compound. The concentration of blood in the blood 6 hours after oral administration is more suitable as a pharmaceutical composition with excellent persistence.

(industrial availability)

The condensed heterocyclic derivative (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof thereof, can modulate gonadotropin-induced hormone release due to superior GnRH antagonism The role of hormones to control the production and secretion of hormones and sex hormones by the gonads, thereby using as a prophylactic or therapeutic agent for sexual hormone-dependent diseases. Therefore, according to the present invention, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, early onset of adolescence, no menstrual disease, premenstrual syndrome, menstrual difficulties, polycystic ovarian syndrome, and erythema can be provided. Lupus, hirsutism, dwarfism, sleep disorders, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumor prevention or A therapeutic agent, a reproductive regulator, a contraceptive, an ovulation inducing agent, or a prophylactic agent after surgery for sex hormone-dependent cancer.

Claims (28)

A condensed heterocyclic derivative or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, which is represented by the general formula (1): [wherein, ring A is a thiophene ring; R ^A is a halogen atom, a cyano group, a nitro group, a C _1-6 alkyl group which may have any group selected from the substituent group (A-1), and may have a substituent selected from the group consisting of The C _2-6 alkenyl group of any group of the group (A-1) may have a C _2-6 alkynyl group or a hydroxyiminomethyl group selected from any group of the substituent group (A-1), and may have is selected from C _1-6 alkylsulfonyl group optionally substituted group of the group (a-1), the group may be substituted with any group selected from groups (a-1) of a C _1-6 alkylsulfinyl acyl , tetrazolyl, OW ¹ , SW ¹ , COW ¹ , COOW ¹ , NHCOW ¹ , NHCONW ² W ³ , NW ² W ³ , CONW ² W ³ or SO ₂ NW ² W ³ (W ¹ ~W ³ independently hydrogen An atom or a C _1-6 alkyl group which may have any group selected from the substituent group (A-1), or W ² and W ³ may be formed together with a nitrogen atom adjacent to which the two are bonded, and may have a substituent selected from the group consisting of a cyclic amine group of any group of the group (B-1); m is an integer of 0 to 3; the ring B is an aryl group or a heteroaryl group; and R ^B is a halogen atom, a cyano group, and may have a substituent group selected from the group consisting of Any of _C1-6 alkyl, OW ⁴ , COW ⁴ , COOW ⁴ or CONW ⁵ W ⁶ (W ⁴ ~W ⁶ independently of (A-2) may independently be a hydrogen atom or may have a group selected from a substituent (A- 2) any group of C _1-6 Group, W ⁵ and W ⁶ may also be adjacent to the nitrogen atom bonded to both form together with any group selected from the group of substituents (B-2) of a cyclic amine); n-represents an integer of 0 to 2; E ¹ is an oxygen atom, a sulfur atom or N-CN; E ² is an oxygen atom or NH; U is a single bond or a C _1-6 alkyl group which may have any group selected from the substituent group (A-2); X is a group represented by Y, -SLY, -OLY, -CO-LY, -SO ₂ -LY or -OZ; (wherein L is any group which may have any group selected from the substituent group (A-2) C _1-6 alkylene; Y is Z or -NW ⁷ W ⁸ [W ⁷ and W ^{8 are} independently a hydrogen atom, and may have a C _1-6 alkyl group selected from any group of the substituent group (A-2) Or Z (but not a hydrogen atom at the same time), or W ⁷ and W ⁸ may form a cyclic amine group which may have any group selected from the substituent group (B-2) together with a nitrogen atom adjacent to the two. a group represented by the formula; Z may be a cycloalkyl group which may have any group selected from the substituent group (B-2), or may be condensed to have a substituent group (B-2). Any of a heterocycloalkyl group, or a condensed ring, which may have an aryl group selected from any group of the substituent group (C), or may have a condensed ring, may have any group selected from the group of substituents (C) Heteroaryl); substituent group (A-1): a halogen atom, a cyano group, a hydroxyl group, C _1-6 alkoxy, C _1-6 alkylthio, amino, mono (di) (C _1-6 alkyl Amino group, carboxyl group, (C _1-6 alkoxy)carbonyl group, amine carbenyl group and mono(di)(C _1-6 alkyl)aminecarbamyl group; substituent group (A-2): halogen atom , cyano, hydroxy, C _1-6 alkoxy, C _1-6 alkyl sulphide, amine, mono(di)(C _1-6 alkane)amine, carboxy, (C _1-6 alkoxy)carbonyl , aminomethyl sulfhydryl, mono (di)(C _1-6 alkyl)amine mercapto, aryl and heteroaryl; substituent group (B-1): pendant oxy group, halogen atom, cyano group, hydroxy group , any group may have a substituent group selected from the group (a-1) of a C _1-6 alkyl group, a cycloalkyl group, any group may have a substituent group selected from (a-1) the C _1-6 alkoxy group, or a C _1-6 alkylthio group substituted with any group selected from the group (a-1) of carboxyl group, may have a (C _1-6 alkoxy group substituted with any group selected from the group (a-1) of the a carbonyl group, an amine carbhydryl group, a mono(di)(C _1-6 alkyl)amine carbaryl group and a fluorenylamino group; a substituent group (B-2): a pendant oxy group, a halogen atom, a cyano group, a hydroxyl group, a C _1-6 alkyl group which may have any group selected from the substituent group (A-2), a cycloalkyl group, may have a selected from a C _1-6 alkoxy group of any group of the substituent group (A-2), a C _1-6 alkyl sulfide which may have any group selected from the substituent group (A-2), a carboxyl group, may have a substituent selected from the group consisting of Any of the (C _1-6 alkoxy)carbonyl group, the amine mercapto group, the mono(di)(C _1-6 alkyl)aminecarbamyl group of any group of the group (A-2), which may have a substituent selected from the group consisting of Any of a group (C), an aryl group, an aryloxy group, a heteroaryl group, a heteroaryloxy group, and a decylamino group; a substituent group (C): a halogen atom, a nitro group, a cyano group, a hydroxyl group, or C with any group selected from the group of substituents (a-2) of _C1-6 alkyl group, a cycloalkyl group, may have a C _1-6 alkoxy group substituted with any group selected from the group (a-2) of the, C _1-6 alkylthio which may be selected from any group of the substituent group (A-2), a carboxyl group, (C _1-6 alkoxy group) which may have any group selected from the substituent group (A-2) Carbonyl, amine mercapto, mono(di)(C _1-6 alkyl)aminecarbamyl, aryl, aryloxy, heteroaryl, heteroaryloxy and decylamino]. The condensed heterocyclic derivative of claim 1 or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein the thiophene ring of ring A is a thiophene ring represented by the following formula; The condensed heterocyclic derivative of the first or second aspect of the invention, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein R ^A is a halogen atom and may have a substituent group selected from _C1-6 alkyl group, COOW ¹ or CONW ² W ³ of any group of A-1) (W ¹ to W ^{3 are} independently a hydrogen atom or C which may have any group selected from the substituent group (A-1) _{The 1-6} alkyl group, or W ² and W ³ may be formed together with a nitrogen atom adjacent to the two to form a cyclic amine group which may have any group selected from the substituent group (B-1). The condensed heterocyclic derivative of claim 3 or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein R ^A is a group selected from the group consisting of a hydroxyl group, a carboxyl group and an amine carbenyl group. Substituted C _1-6 alkyl; carboxy; or amine carbaryl. The condensed heterocyclic derivative of the first or second aspect of the invention, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein m is 0 or 1. The scope of the patent condensed heterocyclic derivative or pharmacologically allowable, Paragraph 5, or of a hydrate of a salt or solvent thereof, wherein, m is 1, the ring system A R ^A bound to the ring A below a thiophene ring at the position; The condensed heterocyclic derivative of the first or second aspect of the invention, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein E ¹ is an oxygen atom. The condensed heterocyclic derivative according to claim 1 or 2, wherein the E ² is an oxygen atom, or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof. The condensed heterocyclic derivative according to claim 1 or 2, wherein the ring B is a benzene ring, a thiophene ring or a pyridine ring, or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof. The condensed heterocyclic derivative according to claim 9 or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein the ring B is any one of the rings represented by the following formula; The condensed heterocyclic derivative of claim 10 or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein n is 1 or 2, and ring B is R ^B bonded to ring B. Any of the rings of the position shown by the following formula; (wherein R ^B is synonymous with the above, and in the case where R ^B is two, two R ^{B 's} may be the same or different). The condensed heterocyclic derivative according to claim 10 or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein the ring B is any one of the rings represented by the following formula; The condensed heterocyclic derivative of the first or second aspect of the invention, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein R ^B is a halogen atom and may have a substituent group selected from a-2) of any C _1-6 alkyl group, OW ⁴ (W ⁴ is a hydrogen atom or a substituent group selected from the group (a-2) to any of C _1-6 alkyl group) or cyano . The condensed heterocyclic derivative according to claim 13 or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein R ^B is a halogen atom and C ₁ may be substituted by a halogen atom. ₆ alkyl, or OW ⁴ (W ⁴ is a hydrogen atom or a C _1-6 alkyl group which may have any group selected from the substituent group (A-2)). The condensed heterocyclic derivative according to claim 14 or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein R ^B is a fluorine atom, a chlorine atom or W ⁴ is a C _1-6 Alkyl OW ⁴ . A condensed heterocyclic derivative or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, according to the first or second aspect of the invention, wherein U is a single bond, a methylene group or an ethylidene group. The condensed heterocyclic derivative of claim 16 or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, wherein U is a single bond, and X is -SLY, -OLY, -CO- A group represented by LY or -SO ₂ -LY (wherein, L and Y are synonymous with the above). The condensed heterocyclic derivative of claim 16 or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, wherein U is a methylene group and X is -Y (where Y is - NW ⁷ W ⁸ [W ⁷ and W ^{8 are} independently a hydrogen atom, may have a C _1-6 alkyl group or a Z (but not a hydrogen atom at the same time) selected from any group of the substituent group (A-2), W ⁷ And W ⁸ may be formed together with a nitrogen atom adjacent to the two to form a cyclic amine group which may have any group selected from the substituent group (B-2)] or a group represented by -OZ (Z is synonymous with the above) ). The condensed heterocyclic derivative of claim 16 or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein U is an ethylidene group and X is -Y (wherein Y is Z) , Z is synonymous with the above). The condensed heterocyclic derivative of the first or second aspect of the invention, or a pharmacologically acceptable salt thereof, or a hydrate or a solvent thereof, wherein L is a C _1-3 alkylene group. The condensed heterocyclic derivative of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a hydrate or a solvent thereof, wherein Z is also condensed and may have a substituent group selected from the group consisting of Any group of aryl groups of (C). A condensed heterocyclic derivative according to claim 1 or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof, which is selected from the group consisting of 5 ^- carboxy-3-{2-fluoro-5-[ 1-(2-Fluoro-6-methoxyphenyl)ethoxy]phenyl}thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione, 5-carboxy-3- [2-Fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]thiophene [3,4-d]pyrimidine-2,4 (1H, 3H)-dione, 5-carboxy-3-[2-chloro-5-(1-methyl-1-phenylethoxy)phenyl]thiophene [3,4-d]pyrimidine-2,4 ( 1H,3H)-dione and 5-carboxy-3-{2-fluoro-5-[2,3-difluoro-6-(2-methoxyethoxy)benzyloxy]phenyl}thiophene [3,4-d]pyrimidine-2,4(1H,3H)-dione. A pharmaceutical composition comprising the condensed heterocyclic derivative of claim 1 or a pharmacologically acceptable salt thereof or a hydrate or a solvent thereof as an active ingredient. For example, in the pharmaceutical composition of claim 23, the gonad-stimulating hormone releases a hormone antagonist. For example, the pharmaceutical composition of claim 23 is a preventive or therapeutic agent for a hormonal-dependent disease, a reproductive regulator, a contraceptive, an ovulation inducing agent, or a prophylactic agent after surgery for sex hormone-dependent cancer. For example, the pharmaceutical composition of claim 25, wherein the sex hormone-dependent disease is caused by prostatic hypertrophy, uterine fibroids, intrauterine Membrane disease, uterine fiber tumor, early onset of puberty, no menstrual disease, premenstrual syndrome, menstrual difficulties, polycystic ovarian syndrome, lupus erythematosus, hirsutism, dwarfism, sleep disorders, acne, alopecia, Diseases selected from the group consisting of Zhaimer, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, and pituitary tumors. For example, the pharmaceutical composition of claim 23 of the patent application is administered orally. The pharmaceutical composition according to claim 23, wherein the pharmaceutical composition further comprises at least one agent selected from the group consisting of: a gonad-stimulating hormone releasing hormone agonist, a chemotherapeutic agent, a peptide gonad Stimulating hormone release hormone antagonists, 5 alpha-reductase inhibitors, alpha adrenergic receptor inhibitors, aromatase inhibitors, para-adrenal androgen production inhibitors, and hormonal therapies.